4.6

CiteScore

2.2

Impact Factor
  • ISSN 1674-8301
  • CN 32-1810/R
Xiangyu Zhang, Yingchao Hu, Bingwei Wang, Shuo Yang. Ferroptosis: Iron-mediated cell death linked to disease pathogenesis[J]. The Journal of Biomedical Research, 2024, 38(5): 413-435. DOI: 10.7555/JBR.37.20230224
Citation: Xiangyu Zhang, Yingchao Hu, Bingwei Wang, Shuo Yang. Ferroptosis: Iron-mediated cell death linked to disease pathogenesis[J]. The Journal of Biomedical Research, 2024, 38(5): 413-435. DOI: 10.7555/JBR.37.20230224

Ferroptosis: Iron-mediated cell death linked to disease pathogenesis

More Information
  • Corresponding author:

    Shuo Yang, Department of Immunology, State Key Laboratory of Reproductive Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Gusu School, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Nanjing, Jiangsu 211166, China. E-mail: shuoyang@njmu.edu.cn

    Bingwei Wang, Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, Jiangsu 210023, China. E-mail: bingweiwang@njucm.edu.cn

  • Received Date: September 18, 2023
  • Revised Date: February 22, 2024
  • Accepted Date: February 28, 2024
  • Available Online: February 29, 2024
  • Published Date: May 28, 2024
  • Ferroptosis is a pattern of iron-mediated regulatory cell death characterized by oxidative damage. The molecular regulatory mechanisms are related to iron metabolism, lipid peroxidation, and glutathione metabolism. Additionally, some immunological signaling pathways, such as the cyclic GMP-AMP synthase-stimulator of the interferon gene axis, the Janus kinase-signal transducer and activator of transcription 1 axis, and the transforming growth factor beta 1-Smad3 axis, may also participate in the regulation of ferroptosis. Studies have shown that ferroptosis is significantly associated with many diseases such as cancer, neurodegenerative diseases, inflammatory diseases, and autoimmune diseases. Considering the pivotal role of ferroptosis-regulating signaling in the pathogenesis of diverse diseases, the development of ferroptosis inducers or inhibitors may have significant clinical potential for the treatment of aforementioned conditions.

  • Intermediate filaments (IFs) in animal cells are one of the three major cytoskeletal filaments: microtubules (MTs, approximately 25 nm in diameter), IFs (10–12 nm), and actin filaments (approximately 6 nm). Unlike MTs and actin filaments, which are assembled from globular subunits, IFs are composed of rod-like dimers formed by a coiled-coil structure[13]. Although keratin (KRT)and neurofilament were discovered before the term "IFs" was coined[45], these filaments were not recognized as IFs at that time. The advent of a technique that enabled the visualization of actin filaments in cells using heavy meromyosin led to the discovery of filaments with a diameter of around 10 nm, which did not bind heavy meromyosin. These were termed "IFs" because their dimensions fell between those of actin filaments and the thick filaments found in striated muscle[6]. The proteins of intermediate-sized filaments in tissue culture cells and animal tissues were identified by immunofluorescent microscopy using specific antibodies against vimentin, keratin, desmin, and brain filament protein[78]. This method allowed for a conclusive differentiation of IFs from MTs and actin filaments.

    The main component of very stable biological structures such as fingernails, hair, wool, horn, and skin stratum corneum is the keratin IFs from dead epithelial cells, which are crosslinked by disulfide bonds. In contrast to these oxidized IFs, the cytoplasmic IFs are dynamic and interact with other cytoskeletons through IF-associated proteins (IFAPs). In epithelial cells, cytoplasmic IFs form transcellular networks through a highly ordered membrane domain called the desmosome, and they also establish connections with the extracellular matrix (ECM) through hemidesmosomes (HDs). These networks are crucial for determining tissue architecture and providing mechanical resilience to cells[9]. In cells undergoing active proliferation and differentiation, IFs are subject to dynamic regulation involving post-translational modifications (PTMs) and interactions with IF-binding partners.

    We have recently reviewed the actin and MT cytoskeletons and cataloged their genes and associated proteins, detailing their names, sizes, functions, associated human diseases, relevant literature, and links to resources like Uniprot and the Protein Atlas database[1011]. However, such a catalog for IFs is unavailable, despite the existence of a number of recent reviews on IFs[1220]. Using this catalog, we will provide an overview of the current understanding of the biological functions of IFs and IFAPs. This overview is essential for identifying gaps in their characterization and understanding IF-mediated mechanotransduction. Additionally, we will consider potential directions for future research. Although plant cells also express IF-like proteins[2122], they are less characterized and will not be described in this review article.

    Given the space limitations and the relatively well-reviewed nature of the topic, an overview of the structure and functions of IFs and IFAPs is included in the supplementary material (available online). Here, we focus on the IF-related diseases, drugs targeting IFs, the mechanics and mechanotransduction of IFs and the nucleus as well as potential future research directions.

    Keratinopathy is associated with mutations in the keratin (types Ⅰ and Ⅱ IFs) gene[2325]. To date, 16 pathogenic gene variants associated with epidermolysis bullosa (EB), a blistering skin disease, have been clearly and comprehensively reviewed[26]. However, the exact molecular mechanisms of how specific keratin mutations cause diseases remains unclear. Nevertheless, these mutations may compromise both structural integrity and mechanical links to hemidesmosomes/desmosomes, and impact cell signaling pathways, including those involved in inflammation and apoptosis[2728]. For example, the homozygous c.1474T > C (p.S492P) mutation in the region determining the tail domain of KRT5 is associated with epidermolysis bullosa simplex (EBS), a genetic skin disorder characterized by fragile skin that easily blisters in response to minor friction or trauma. This mutation hampers the proper assembly of keratin IFs, presumably because of a change in the peptide bond angle at the 492nd residue caused by the substitution to proline, and inhibits the MAPK signaling through an unknown mechanism[29]. Although it is not confirmed, mutants of KAPs likely also cause keratinopathy, because mutations of other KAP genes, such as plectin, cause a mutant of EB, the best-studied keratinopathy[30]. Disruption of the IF network leads to acantholysis within the basal and suprabasal layers of the epidermis, ultimately resulting in blistering and/or hyperkeratinization of the skin[31].

    Interestingly, keratinopathies are not merely diseases caused by abnormalities in mechanical strength because of mutations in the keratin gene; there are also heterogeneous diseases presenting multiple manifestations ranging from epidermal fragility to epidermal hyperproliferation[32].

    Desminopathy is a subtype of myofibrillar myopathy caused by the loss or mutations of the desmin (type Ⅲ IF) gene and is characterized by protein aggregates accumulating in muscle fibers[3335]. Heat shock proteins (HSPs), such as HSP22, HSP27, and α-crystallins, prevent protein accumulation and aggregation, and the HSP inducer, geranylgeranylacetone may inhibit the progression of desmin-related cardiomyopathy[3637]. Nevertheless, there are currently no clear and effective treatments for desminopathy; however, some complications may be prevented with early diagnosis and the use of pacemakers[35].

    Diseases associated with type Ⅲ IFs, including desmin, GFAP, vimentin, peripherin, and syncoilin, could be caused by modifications from oxidants and electrophiles, because theoxidation of their conserved cysteine residue in the coil 2 (2B) domain induces structural rearrangements[3839]. Therefore, type Ⅲ IFs act as sensors for oxidative and electrophilic stress. The plant poisoning vermeersiekte, which mainly occurs in sheep, is caused by several Geigeria (G.) species that produce sesquiterpene lactones. Sesquiterpene lactones such as ivalin and parthenolide induce aggregation of desmin[40].

    Loss, up-regulation, or mutations of type Ⅳ IFs, such as alpha-internexin, neurofilaments, nestin, and synemin cause various diseases[4143]. Moreover, an increase in INA levels is noted in certain gliomas, especially in oligodendrogliomas. Therefore, INA expression seems to serve as a reliable prognostic marker[44]. Mutations of the neurofilament genes cause several neuroaxonal and neuropsychiatric disorders characterized by disrupted subunit assembly and neurofilament aggregation[45]. Typically, mutations in NEFL cause Charcot–Marie–Tooth disease (CMT) type 2E (characterized by axonal damage in the peripheral nerves, leading to muscle weakness and sensory loss), CMT1F (which involves demyelination and slowed nerve conduction), and dominant-intermediate CMT (DI-CMTG) (a form with both axonal and demyelinating features). Mutations in NEFH are associated with CMT2CC, an axonal variant of CMT that also results in progressive muscle weakness and sensory impairment in the limbs[4648]. Although mutations in over 100 genes may lead to CMT, thecases related to mutations in the neurofilament genes account for only a small portion of the diagnosed CMT cases[4649]. CMT primarily affects the motor and sensory nerves, leading to muscle weakness and atrophy. The reported mutations in NEFL related to CMT are mostly missense mutations, as well as nonsense, frameshift, and deletion mutations[50]. However, these mutations span the entire length of NEFL, and their locations are independent of CMT types[4647]. In contrast, mutations in NEFH frequently occur in the C-terminal portion of the tail domain[46]. Increased expression of nestin in melanoma is associated with an aggressive course of the disease and poor prognosis[51]. A mutation of the synemin gene was reported in the ulnar-mammary-like syndrome that is associated with left ventricular tachycardia and other cardiac and skeletal myopathies[5253].

    Mutations of the lens-specific type Ⅵ IF genes, BFSP1 and BFSP2, cause cataracts[5457]. To better understand disease mechanisms and treatment, eye organoids have been generated; however, their application to vision research remains in its infancy[58].

    Laminopathies are associated with mutations in the genes coding for nuclear lamins (type Ⅴ IF) and lamin-binding proteins[5960]. LMNA is among the most mutated human genes, and its mutations lead to numerous heritable diseases[6162]. For example, it was recently found that the transcription factor TEAD1 is trapped at the nuclear membrane by mutant lamin A/C (Q353R), which causes dilated cardiomyopathy[63] as previously reported[64]. Because B-type lamins are involved in a wide range of nuclear functions such as DNA replication and repair, as well as chromatin regulation, mutations in their genes or up- or down-regulation of their expression levels are critical for the onset of several diseases. For example, the duplication of LMNB1 is associated with the adult-onset leukodystrophy, and the altered LMNB1 expression leads to senescence. Mutations of LMNB1 and LMNB2 also cause various diseases including neurodegenerative diseases and lipodystrophy. Moreover, mutations in the lamin-associated genes, such as LBR, may also cause laminopathies, including Greenberg Dysplasia, which is characterized by abnormal bone development and fluid accumulation, and Pelger-Huët anomaly, a benign genetic condition marked by abnormal nuclear shapes in white blood cells[65].

    Importantly, IFs also interact with proteins and nucleotides from pathogens to facilitate their entry into host cells and their replication, providing a potential drug target[6672].

    More than 80 human diseases are linked to mutations in the genes coding for IF proteins, referred to as IF-pathies, and there are currently no available treatments that directly target IFs to address these disorders[73]. In fact, there are not many available compounds that act on IFs, even for research purposes, compared with those available for other cytoskeletal polymers[1011]. Nevertheless, owing to their diverse biological functions, some small molecules that specifically affect IFs have been discovered from natural products and synthesized. For example, retinoids and sulforaphane obtained from plants have the potential to restore skin integrity by selectively increasing the expression of normal keratins (e.g., type Ⅱ keratin KRT6, and type Ⅰ keratins KRT16 and KRT17, which are typically expressed during wound healing or in response to skin stress). This may help compensate for the mutants seen in EBS (commonly involving mutations in type Ⅱ keratin KRT5 and type Ⅰ keratin KRT14) in mouse models, highlighting the functional redundancy within the keratin family as a key factor in modulating the severity of phenotypes[7476]. Recent studies have shown that ferulic acid promotes wound healing by inducing KRT6A (type Ⅱ keratin), inhibiting beta-catenin in keratinocytes, and activating nuclear factor erythroid-2-related factor 2 at the wound edge[77] . Therefore, sulforaphane may be effective in addressing EBS caused by type I keratin mutations, while ferulic acid could potentially treat EBS resulting from type Ⅱ keratin mutations. Midostaurin (https://pubchem.ncbi.nlm.nih.gov/compound/9829523) facilitates the restoration of proper structure in IFs that incorporate mutated keratins within hepatocytes. This is achieved by enhancing their binding to a non-muscle myosin heavy chain and modifying the phosphorylation sites on keratins and desmoplakin, with the aim of treating patients afflicted by EBS[7879]. Peptide-drug conjugates targeting KRT1 may inhibit triple-negative breast cancer in mice[80]. Mutations in the keratin genes associated with diseases induce PTMs in both keratins and their associated proteins, contributing to the progression of the disease. Therefore, there is a therapeutic opportunity in targeting specific PTMs and their pathways[25]. For instance, the expression profiling signature of EBS was countered by Akt/mTOR and PI3K inhibitors. Furthermore, EBS patients undergoing topical treatment with sirolimus, an mTOR inhibitor, exhibited significant clinical improvement and a notable reduction in keratoderma[81].

    Aggregation of desmin (type Ⅲ) may be reduced by antioxidants, including alpha-lipoic acid, α-tocopherol, acetyl-α-tocopherol, curcumin, and colchicine, as well as by inhibition of the Rac1 pathway (e.g., NSC23766), stimulation of macroautophagy (e.g., mTOR inhibitor pp242), and induction of heat-shock proteins (e.g., geldanamycin derivative 17-DMAG)[82]. Expression and aggregation of another type Ⅲ IF, GFAP, may be reduced by phenytoin or carbamazepine. Therefore, these drugs have a potential therapeutic role in clinical management of Alexander's disease, which is related to heterozygous mutations of GFAP[83]. The major type Ⅲ IF, vimentin, is a potential molecular target for cancer therapy[84]. For example, a small molecule, FiVe1 (https://pubchem.ncbi.nlm.nih.gov/compound/20922966), targets vimentin to promote its disorganization and phosphorylation during metaphase, leading to mitotic catastrophe and the loss of stemness. Therefore, FiVe1 has the potential to target a broad range of mesenchymal cancers[85]. Since cell surface vimentin is also involved in host cell interactions with pathogens, targeting such vimentin with antibodies or chemical agents that could modulate these interactions may potentially interfere with microbial pathogenesis[86]. For example, withaferin A, a compound derived from Withania somnifera, forms a direct covalent bond with vimentin by binding to Cys328 in the coil 2B domain, leading to the aggregation of vimentin filaments[8788]. Similarly, withaferin A also covalently binds to human GFAP at Cys294, which resulting in changes to its conformation, stability, and assembly. Following this covalent binding, withaferin A triggers the down-regulation of GFAP expression at the transcriptional or post-transcriptional level, although the exact mechanism of this down-regulation remains unclear[89]. Given the high degree of similarity between the 2B region of desmin and that of vimentin, it has been proposed that withaferin A might also covalently bind to desmin[90]. Additionally, withaferin A also inhibits the phosphorylation of vimentin Ser56[91]. Since vimentin and GFAP are overexpressed during gliosis, drugs targeting these proteins may have some therapeutic potential for gliosis-dependent central nervous system traumatic injury[8992]. For example, withaferin A exhibits antiangiogenic and antitumor properties, along with various other biological activities, likely attributable to its interaction with diverse cellular targets. Ajoene, a phytochemical found in garlic, also covalently binds to vimentin at the same cysteine residue as withaferin A, disrupting the cellular vimentin network and reducing cell migration[93]. Furthermore, other natural products have been identified for their interactions with vimentin as well. Statins such as simvastatin and mevastatin promote the bundling of vimentin and exhibit selective cytotoxicity toward mesenchymal breast cancer cells expressing vimentin[94]. ALD-R491 regulates vimentin filament stability and solubility, affecting cell contractile force, cell migration speed, and directionality[95]. Lastly, the vimentin-targeted radiopeptide 99m Tc-HYNIC-(tricine/EDDA)-VNTANST shows some promise as a tool for imaging pulmonary fibrosis[96].

    Nestin becomes a target for shikonin, a natural naphthoquinone compound derived from the roots of Lithospermum erythrorhizon, known for its anti-inflammatory, anticancer, and antioxidant properties that impact the hypoxia-induced proliferation of pulmonary artery smooth muscle cells[97]. Natural products like salvianolic acids, tetramethylpyrazine, and resveratrol may induce nestin expression, although the precise mechanisms are not fully understood. The modulation of nestin through the transcriptional region by LncRNA ENST869 influences the pharmacological effects of Chidamide in breast cancer cells[98]. To date, there has not been any development of drugs that specifically target other type Ⅳ IFs.

    Pharmacological disruption of the binding between progerin and lamin A/C using JH4, a small molecule that reduces the toxic effects of progerin accumulation and improves nuclear structure, has a beneficial effect on alleviating the HGPS phenotype[99]. An improved progerin inhibitor known as SLC-D011, also referred to as progerinin (https://pubchem.ncbi.nlm.nih.gov/substance/440089748), has been shown to reduce progerin expression and improve age-related phenotypes in model systems[100101]. Farnesyltransferase inhibitors have the capacity of interfering with the abnormal splicing of the LMNA gene, which leads to the accumulation of progerin[102]. Additionally, the activation of AMP-activated protein kinase by metformin, resveratrol, or berberine may reduce progerin production and accumulation by mitigating aberrant splicing[103]. Furthermore, the induction of autophagy through various means such as rapamycin, retinoids, proteasome inhibition, and sulforaphane facilitates the clearance of progerin, resulting in the reversal of aging-related defects in HGPS patient skin fibroblasts and animal models[104105]. While not directly aimed at lamins, the inhibition of MEK1/2, JNK, and p38α has been observed to alleviate symptoms resulting from LMNA mutations[106].

    Rosmarinic acid may significantly ameliorate cataract formation and oxidative damage in the lens, and increase the protein expression of filensin[107]. However, how rosmarinic acid acts on type Ⅵ IFs is not known.

    As cells invade the surrounding tissues, they often undergo significant deformations. While the structural integrity of eukaryotic cells under minor deformations relies on actin filaments, MTs, and IFs, it is the IF networks that play a dominant role in cytoplasmic mechanics and sustain cell viability under substantial deformations[17,19,108110]. The mechanical characteristics of IFs (persistence length ~ 0.2–2 μm, no elasticity loss even at an 80% strain) differ considerably from those of actin filaments (persistence length 3–18 μm, elasticity loss at ~20% strain) or MTs (persistence length >1 mm, elasticity loss at ~50% strain)[108, 111113]. Therefore, single IFs are significantly flexible, and nuclear and cytoplasmic IFs also exhibit remarkable stretchability[114]. Depending on the experimental conditions, IFs may be stretched up to 3.6-fold before reaching a breaking point[110,112]. In addition to their high elasticity, IFs display a strain-stiffening response. IF proteins possess the unique ability to undergo molecular structural changes in response to external forces[115]. The initial elasticity observed at low strains largely results from the stretching of the coiled-coil α-helical domains within the IF proteins[116]. Further extension of the α-helical domains induces additional conformational changes, eventually leading to the formation of β-sheet structures. Consistent with this in vitro observation, a cysteine-reactive fluorescent probe revealed conformational changes in vimentin in cells treated with a myosin inhibitor[117], and Raman microscopy provided some visional evidence that the secondary structure of vimentin changes within cells[118]. The conformational changes of vimentin reflect the filaments' ability to absorb energy within the mechanical range (up to 500 pN) where most physiological processes occur. Rapid stretching may result in filament stiffening at around 50% strain, whereas at lower velocities, IFs do not exhibit stiffness until they are stretched to approximately 200%[116]. The mechanical characteristics of IF networks encompass both the inherent mechanics of single molecules and the crosslinking between individual IF molecules. For example, recent experiments in single-cell nanomechanics have illustrated that the removal of type Ⅰ or type Ⅱ keratins leads to a reduction of over 50% in Young's modulus of keratinocytes[119120]. In contrast, the overexpression of desmin or vimentin results in an increase in cell stiffness[121]. More recent research has highlighted that vimentin IFs play a critical role in determining cell resilience[114] and safeguard cells from nuclear rupture and DNA damage during cell migration[122].

    Both keratin and vimentin play roles in mechanosensing[123124]. For instance, when keratinocytes encounter varying levels of matrix stiffness, they respond by establishing a robust network of keratin bundles. This network is less susceptible to deformation, resulting in an enhanced cell stiffness. In contrast, cells lacking vimentin exhibit impaired spreading on viscous substrates created using hydrogels with controlled elastic and viscoelastic characteristics[124]. More recently, vimentin IFs have been shown to modulate cellular stress by facilitating actomyosin-based force transmission and reinforcing MT networks under compression[125].

    IFAPs may also mediate mechanotransduction. For example, the plakin domain of Caenorhabditis elegans VAB-10/plectin acts as a hub in a mechanotransduction pathway to promote morphogenesis[126127]. Additionally, the loss of plectin decreases fibroblast stiffness and disrupts force transmission[128]. In keratinocytes, plectin also regulates nuclear mechanotransduction[129](Fig. 1). Although it is likely that more players are involved in mechanotransduction, the lack of structural and biochemical analysis regarding the interaction of IF with IFAPs hampers the progress of this field. However, identifying additional cryptic binding sites that may be activated by mechanical forces is a challenging endeavor.

    Figure  1.  Mechanotransduction mediated by conformational changes of the plakin domain of plectin.
    A: Molecular structure of plectin domains. B: A model of how mechanical force exposes the SH3 domain in the plakin domain of Caenorhabditis elegans VAB-10/plectin. It is hypothesized that this exposure recruits an as-yet unidentified signaling molecule to transmit a signal in response to mechanical stimulation[127].

    While an increasing number of studies have shown that IFs and IFAPs play a role in mechanotransduction, and their folded structures suggest that mechanical forces may induce unfolding and trigger biochemical signaling, this field remains in its early stages. Potential directions for future research are outlined in the final section of this review.

    Both lamin A and lamin B1 contribute to nuclear elasticity, although lamin A primarily determines nuclear viscosity[130]. Lamin filaments exhibit the ability to undergo reversible deformation within a low-force range (less than 500 pN), effectively serving as shock absorbers. Additionally, these filaments may endure sustained forces of up to 2 nN. These characteristics are essential for preventing filament breakage and the network failure[131].

    Lamins transmit external and internal mechanical information to the nucleus through the cytoskeleton and the LINC complex (Supplementary Fig. 4, available online). The transmitted forces alter nuclear structure, chromatin organization, and gene expression[132].

    IFs play a vital role in various fundamental biological processes. To systematically organize the genes associated with IFs and the IF-associated proteins (IFAPs), we have compiled a comprehensive list of all known IF (71) and IFAP (307) genes, excluding splice variants. In this review, we refrained from conducting an in-depth evaluation of each IFAP, as many comprehensive articles reviewing these proteins are already available, as indicated in Supplementary Table 2. However, it is worth noting that the structural and biological functions of numerous IFAPs still await further characterization. For example, only about 43% (131 out of 307) of the known IFAPs have been demonstrated to directly interact with IFs in vitro. Future research endeavors are necessary to support the direct interactions of the remaining 174 IFAPs with IFs and to delve into more intricate details of these interactions. Some IFAPs lack well-defined IF interaction domains, and it is possible that only specific splice variants engage with IFs. Identifying and characterizing IFAPs remains a labor-intensive task that demands extensive biochemical work in wet laboratories. Currently, computational algorithms for discovering new IFAPs using IF-binding motifs are not available. Despite these challenges, more IFAPs are likely to be discovered in the future, particularly those enzymes that are involved in the post-translational modifications of IFs. Such structural and biochemical characterizations are crucial for unraveling the molecular mechanisms of mechanotransduction.

    Considering that IFs and IFAPs may experience mechanical stress from both external and internal forces, it is conceivable that such stress may expose previously unrecognized binding domains, which have not been considered drug targets before. Because of their fundamental roles in normal cells, the specific manipulation of IF systems for therapeutic purposes presents a formidable challenge. Nonetheless, some research groups have initiated screenings for drugs that modulate IFs and IFAPs[85,133134]. To facilitate these efforts, it is essential to gain a deeper understanding of the molecular mechanisms that govern IF dynamics, mechanotransduction, and their interactions with IFAPs. This involves exploring how mechanical forces induce changes in protein conformation, potentially revealing new druggable sites. Moreover, the development of more advanced screening techniques, such as high-throughput platforms or structure-based drug design, will be crucial for identifying compounds that may specifically target these newly exposed binding domains without affecting normal cellular functions. Such advancements could pave the way for precise therapeutic targeting of IFs and IFAPs in various disease contexts.

    Finally, drawing on our previous research experience with mechanotransduction mediated by the actin cytoskeleton and the functions of IFAPs summarized in Supplementary Table 2 (available online), as well as the mechanical and structural properties of IFs described above, we have proposed our hypotheses and remaining issues regarding mechanotransduction involving IFs.

    1. Since IFs may be stretched up to 3.6-fold before reaching a breaking point, significant structural changes likely occur in IF molecules under mechanical stress. These structural changes would regulate the interaction with IFAPs, but the following issues need clarification: (a) Stretching of IFs induces conformational changes in the coiled-coil α-helical domains but likely has little impact on the structure of the head and tail domains of IFs (Supplementary Fig. 2, available online). As summarized in Supplementary Table 2, only a limited number of IFAPs have been thoroughly characterized regarding the specific IF domains that they bind to. Identifying these binding domains is essential to understanding how mechanical forces may influence IF-IFAP interactions. Furthermore, the current molecular structures of IF-IFAP complexes do not clearly suggest a role in mechanotransduction. Although AlphaFold predictions may offer valuable insights into these complex structures, a high-throughput screening approach is still needed to identify the specific mechano-sensing domains.(b) The biophysical properties of IFs have been measured using purified proteins, but it remains unclear how IFs deform under physiological forces. Developing a quantitative force sensor is essential (e.g., [135]), but designing such a sensor requires identifying the mechano-sensing domain and understanding its structure.

    2. Mechanosensitive transcription factors or co-factors, such as YAP1, shuttle between the nucleus and cytosol, with this translocation regulated by the actin cytoskeleton[136137]. Similarly, the translocation of HNRNPK from the nucleus to the cytoplasm promotes cell proliferation and cancer metastasis. KRT19 directly interacts with HNRNPK and sequesters it in the cytoplasm. In the absence of KRT19, HNRNPK localizes to the nucleus, resulting in a reduced cell proliferation[138].

    As summarized in Supplementary Table 2, several IFAPs, such as HNRNPC, CRHBP, HNRNPA1, PPARG, and RNF26, are also localized in the nucleus despite their interactions with vimentin. Therefore, it is possible that the nucleocytoplasmic shuttling of these proteins is regulated by mechanical forces, as these forces may influence the interaction between IFAPs and IFs, as discussed above.

    3. When mechanical forces are applied to the tissue, it strengthens to withstand them. For instance, calluses contain keratin, which reinforces and protects the skin against mechanical stress[139]. This suggests that mechanical stress triggers the gene expression of IFs and IFAPs. However, the exact mechanotransduction pathways remain to be discovered, requiring future research that may ultimately aid in designing small-molecule inhibitors.

    None.

    This work was supported by the National Key Research and Development Program of China (Grant No. 2022YFA1303900 to S.Y.), the National Natural Science Foundation of China (Grant Nos. 32270921 and 82070567 to S.Y., and 82204354 to Y.H.), the Open Project of State Key Laboratory of Reproductive Medicine of Nanjing Medical University (Grant No. SKLRM-2021B3 to S.Y.), the Talent Cultivation Project of "Organized Scientific Research" of Nanjing Medical University (Grant No. NJMURC20220014 to S.Y.), the Natural Science Foundation of Jiangsu Province (Grant No. BK20221352 to B.W.), the Jiangsu Provincial Outstanding Postdoctoral Program (Grant No. 2022ZB419 to Y.H.) and the Postdoctoral Research Funding Project of Gusu School (Grant No. GSBSHKY202104 to Y.H.), and the China Postdoctoral Science Foundation (Grant No. 2023T160329 to Y.H.).

    CLC number: R329.25, Document code: A

    The authors reported no conflict of interests.

  • [1]
    Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060–1072. doi: 10.1016/j.cell.2012.03.042
    [2]
    Yang WS, Stockwell BR. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells[J]. Chem Biol, 2008, 15(3): 234–245. doi: 10.1016/j.chembiol.2008.02.010
    [3]
    Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer[J]. Nat Rev Cancer, 2022, 22(7): 381–396. doi: 10.1038/s41568-022-00459-0
    [4]
    Reichert CO, de Freitas FA, Sampaio-Silva J, et al. Ferroptosis mechanisms involved in neurodegenerative diseases[J]. Int J Mol Sci, 2020, 21(22): 8765. doi: 10.3390/ijms21228765
    [5]
    Ni L, Yuan C, Wu X. Targeting ferroptosis in acute kidney injury[J]. Cell Death Dis, 2022, 13(2): 182. doi: 10.1038/s41419-022-04628-9
    [6]
    Tang D, Chen X, Kang R, et al. Ferroptosis: molecular mechanisms and health implications[J]. Cell Res, 2021, 31(2): 107–125. doi: 10.1038/s41422-020-00441-1
    [7]
    Wang Y, Liu Y, Liu J, et al. NEDD4L-mediated LTF protein degradation limits ferroptosis[J]. Biochem Biophys Res Commun, 2020, 531(4): 581–587. doi: 10.1016/j.bbrc.2020.07.032
    [8]
    Dolma S, Lessnick SL, Hahn WC, et al. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells[J]. Cancer Cell, 2003, 3(3): 285–296. doi: 10.1016/S1535-6108(03)00050-3
    [9]
    Yang WS, Kim KJ, Gaschler MM, et al. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis[J]. Proc Natl Acad Sci U S A, 2016, 113(34): E4966–E4975. doi: 10.1073/pnas.1603244113
    [10]
    Chen X, Kang R, Kroemer G, et al. Ferroptosis in infection, inflammation, and immunity[J]. J Exp Med, 2021, 218(6): e20210518. doi: 10.1084/jem.20210518
    [11]
    Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk[J]. Cell Death Differ, 2019, 26(1): 99–114. doi: 10.1038/s41418-018-0212-6
    [12]
    Bertheloot D, Latz E, Franklin BS. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death[J]. Cell Mol Immunol, 2021, 18(5): 1106–1121. doi: 10.1038/s41423-020-00630-3
    [13]
    Chen X, Comish PB, Tang D, et al. Characteristics and biomarkers of ferroptosis[J]. Front Cell Dev Biol, 2021, 9: 637162. doi: 10.3389/fcell.2021.637162
    [14]
    Xie Y, Hou W, Song X, et al. Ferroptosis: process and function[J]. Cell Death Differ, 2016, 23(3): 369–379. doi: 10.1038/cdd.2015.158
    [15]
    Cui S, Ghai A, Deng Y, et al. Identification of hyperoxidized PRDX3 as a ferroptosis marker reveals ferroptotic damage in chronic liver diseases[J]. Mol Cell, 2023, 83(21): 3931–3939.e5. doi: 10.1016/j.molcel.2023.09.025
    [16]
    Friedmann Angeli JP, Schneider M, Proneth B, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice[J]. Nat Cell Biol, 2014, 16(12): 1180–1191. doi: 10.1038/ncb3064
    [17]
    Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor[J]. Nature, 2019, 575(7784): 693–698. doi: 10.1038/s41586-019-1707-0
    [18]
    Mao C, Liu X, Zhang Y, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer[J]. Nature, 2021, 593(7860): 586–590. doi: 10.1038/s41586-021-03539-7
    [19]
    Soula M, Weber RA, Zilka O, et al. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers[J]. Nat Chem Biol, 2020, 16(12): 1351–1360. doi: 10.1038/s41589-020-0613-y
    [20]
    Wang Y, Wei Z, Pan K, et al. The function and mechanism of ferroptosis in cancer[J]. Apoptosis, 2020, 25(11-12): 786–798. doi: 10.1007/s10495-020-01638-w
    [21]
    Vila IK, Chamma H, Steer A, et al. STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses[J]. Cell Metab, 2022, 34(1): 125–139.e8. doi: 10.1016/j.cmet.2021.12.007
    [22]
    Yu X, Zhu D, Luo B, et al. IFNγ enhances ferroptosis by increasing JAK-STAT pathway activation to suppress SLCA711 expression in adrenocortical carcinoma[J]. Oncol Rep, 2022, 47(5): 97. doi: 10.3892/or.2022.8308
    [23]
    Wei T, Zhang M, Zheng X, et al. Interferon-γ induces retinal pigment epithelial cell Ferroptosis by a JAK1-2/STAT1/SLC7A11 signaling pathway in Age-related Macular Degeneration[J]. FEBS J, 2022, 289(7): 1968–1983. doi: 10.1111/febs.16272
    [24]
    Song SH, Han D, Park K, et al. Bone morphogenetic protein-7 attenuates pancreatic damage under diabetic conditions and prevents progression to diabetic nephropathy via inhibition of ferroptosis[J]. Front Endocrinol, 2023, 14: 1172199. doi: 10.3389/fendo.2023.1172199
    [25]
    Louandre C, Ezzoukhry Z, Godin C, et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib[J]. Int J Cancer, 2013, 133(7): 1732–1742. doi: 10.1002/ijc.28159
    [26]
    Lachaier E, Louandre C, Godin C, et al. Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors[J]. Anticancer Res, 2014, 34(11): 6417–6422. https://ar.iiarjournals.org/content/34/11/6417.long
    [27]
    Sun X, Ou Z, Chen R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells[J]. Hepatology, 2016, 63(1): 173–184. doi: 10.1002/hep.28251
    [28]
    Chen D, Fan Z, Rauh M, et al. ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner[J]. Oncogene, 2017, 36(40): 5593–5608. doi: 10.1038/onc.2017.146
    [29]
    Lu Y, Qin H, Jiang B, et al. KLF2 inhibits cancer cell migration and invasion by regulating ferroptosis through GPX4 in clear cell renal cell carcinoma[J]. Cancer Lett, 2021, 522: 1–13. doi: 10.1016/j.canlet.2021.09.014
    [30]
    Duce JA, Tsatsanis A, Cater MA, et al. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease[J]. Cell, 2010, 142(6): 857–867. doi: 10.1016/j.cell.2010.08.014
    [31]
    Bao W, Pang P, Zhou X, et al. Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer's disease[J]. Cell Death Differ, 2021, 28(5): 1548–1562. doi: 10.1038/s41418-020-00685-9
    [32]
    Mahoney-Sánchez L, Bouchaoui H, Ayton S, et al. Ferroptosis and its potential role in the physiopathology of Parkinson's disease[J]. Prog Neurobiol, 2021, 196: 101890. doi: 10.1016/j.pneurobio.2020.101890
    [33]
    Xu M, Tao J, Yang Y, et al. Ferroptosis involves in intestinal epithelial cell death in ulcerative colitis[J]. Cell Death Dis, 2020, 11(2): 86. doi: 10.1038/s41419-020-2299-1
    [34]
    Xu J, Liu S, Cui Z, et al. Ferrostatin-1 alleviated TNBS induced colitis via the inhibition of ferroptosis[J]. Biochem Biophys Res Commun, 2021, 573: 48–54. doi: 10.1016/j.bbrc.2021.08.018
    [35]
    Shou Y, Yang L, Yang Y, et al. Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation[J]. Cell Death Dis, 2021, 12(11): 1009. doi: 10.1038/s41419-021-04284-5
    [36]
    Li P, Jiang M, Li K, et al. Glutathione peroxidase 4–regulated neutrophil ferroptosis induces systemic autoimmunity[J]. Nat Immunol, 2021, 22(9): 1107–1117. doi: 10.1038/s41590-021-00993-3
    [37]
    Cheng Y, Song Y, Chen H, et al. Ferroptosis mediated by lipid reactive oxygen species: a possible causal link of neuroinflammation to neurological disorders[J]. Oxid Med Cell Longev, 2021, 2021: 5005136. https://www.hindawi.com/journals/omcl/2021/5005136/
    [38]
    Kirtonia A, Sethi G, Garg M. The multifaceted role of reactive oxygen species in tumorigenesis[J]. Cell Mol Life Sci, 2020, 77(22): 4459–4483. doi: 10.1007/s00018-020-03536-5
    [39]
    Yan B, Ai Y, Sun Q, et al. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1[J]. Mol cell, 2021, 81(2): 355–369.e10. doi: 10.1016/j.molcel.2020.11.024
    [40]
    Zhang C, Zhang F. Iron homeostasis and tumorigenesis: molecular mechanisms and therapeutic opportunities[J]. Protein Cell, 2015, 6(2): 88–100. doi: 10.1007/s13238-014-0119-z
    [41]
    Wang Y, Yu L, Ding J, et al. Iron metabolism in cancer[J]. Int J Mol Sci, 2018, 20(1): 95. doi: 10.3390/ijms20010095
    [42]
    Mancias JD, Wang X, Gygi SP, et al. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy[J]. Nature, 2014, 509(7498): 105–109. doi: 10.1038/nature13148
    [43]
    Gao M, Monian P, Pan Q, et al. Ferroptosis is an autophagic cell death process[J]. Cell Res, 2016, 26(9): 1021–1032. doi: 10.1038/cr.2016.95
    [44]
    Hou W, Xie Y, Song X, et al. Autophagy promotes ferroptosis by degradation of ferritin[J]. Autophagy, 2016, 12(8): 1425–1428. doi: 10.1080/15548627.2016.1187366
    [45]
    Liu Z, Lv X, Yang B, et al. Tetrachlorobenzoquinone exposure triggers ferroptosis contributing to its neurotoxicity[J]. Chemosphere, 2021, 264: 128413. doi: 10.1016/j.chemosphere.2020.128413
    [46]
    Ingold I, Berndt C, Schmitt S, et al. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis[J]. Cell, 2018, 172(3): 409–422.e21. doi: 10.1016/j.cell.2017.11.048
    [47]
    Angeli JPF, Conrad M. Selenium and GPX4, a vital symbiosis[J]. Free Radical Biol Med, 2018, 127: 153–159. doi: 10.1016/j.freeradbiomed.2018.03.001
    [48]
    Ursini F, Maiorino M. Lipid peroxidation and ferroptosis: the role of GSH and GPx4[J]. Free Radical Biol Med, 2020, 152: 175–185. doi: 10.1016/j.freeradbiomed.2020.02.027
    [49]
    Griffith OW. Biologic and pharmacologic regulation of mammalian glutathione synthesis[J]. Free Radical Biol Med, 1999, 27(9-10): 922–935. doi: 10.1016/S0891-5849(99)00176-8
    [50]
    Griffith OW, Mulcahy RT. The enzymes of glutathione synthesis: γ-glutamylcysteine synthetase[M]//Purich DL. Advances in Enzymology and Related Areas of Molecular Biology: Mechanism of Enzyme Action, Part A. New York: Wiley, 1999: 209–267.
    [51]
    Hao S, Liang B, Huang Q, et al. Metabolic networks in ferroptosis[J]. Oncol Lett, 2018, 15(4): 5405–5411. doi: 10.3892/ol.2018.8066
    [52]
    Liu L, Liu R, Liu Y, et al. Cystine-glutamate antiporter xCT as a therapeutic target for cancer[J]. Cell Biochem Funct, 2021, 39(2): 174–179. doi: 10.1002/cbf.3581
    [53]
    Liu M, Zhu W, Pei D. System Xc: a key regulatory target of ferroptosis in cancer[J]. Invest New Drugs, 2021, 39(4): 1123–1131. doi: 10.1007/s10637-021-01070-0
    [54]
    Lin Z, Liu J, Long F, et al. The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis[J]. Nat Commun, 2022, 13(1): 7965. doi: 10.1038/s41467-022-35707-2
    [55]
    Vasan K, Werner M, Chandel NS. Mitochondrial metabolism as a target for cancer therapy[J]. Cell Metab, 2020, 32(3): 341–352. doi: 10.1016/j.cmet.2020.06.019
    [56]
    Mishima E, Nakamura T, Zheng J, et al. DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition[J]. Nature, 2023, 619(7968): E9–E18. doi: 10.1038/s41586-023-06269-0
    [57]
    Crabtree MJ, Tatham AL, Hale AB, et al. Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways[J]. J Biol Chem, 2009, 284(41): 28128–28136. doi: 10.1074/jbc.M109.041483
    [58]
    Kraft VAN, Bezjian CT, Pfeiffer S, et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling[J]. ACS Cent Sci, 2019, 6(1): 41–53. doi: 10.1021/acscentsci.9b01063
    [59]
    Dodson M, Castro-Portuguez R, Zhang DD. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis[J]. Redox Biol, 2019, 23: 101107. doi: 10.1016/j.redox.2019.101107
    [60]
    Anandhan A, Dodson M, Schmidlin CJ, et al. Breakdown of an ironclad defense system: the critical role of NRF2 in mediating ferroptosis[J]. Cell Chem Biol, 2020, 27(4): 436–447. doi: 10.1016/j.chembiol.2020.03.011
    [61]
    Hassannia B, Wiernicki B, Ingold I, et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma[J]. J Clin Invest, 2018, 128(8): 3341–3355. doi: 10.1172/JCI99032
    [62]
    Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal[J]. Oxid Med Cell Longev, 2014, 2014: 360438. https://www.hindawi.com/journals/omcl/2014/360438/
    [63]
    Lee JY, Nam M, Son HY, et al. Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer[J]. Proc Natl Acad Sci U S A, 2020, 117(51): 32433–32442. doi: 10.1073/pnas.2006828117
    [64]
    Yamane D, Hayashi Y, Matsumoto M, et al. FADS2-dependent fatty acid desaturation dictates cellular sensitivity to ferroptosis and permissiveness for hepatitis C virus replication[J]. Cell Chem Biol, 2022, 29(5): 799–810.e4. doi: 10.1016/j.chembiol.2021.07.022
    [65]
    Nassar ZD, Mah CY, Dehairs J, et al. Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis[J]. Elife, 2020, 9: e54166. doi: 10.7554/eLife.54166
    [66]
    Magtanong L, Ko PJ, To M, et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state[J]. Cell Chem Biol, 2019, 26(3): 420–432.e9. doi: 10.1016/j.chembiol.2018.11.016
    [67]
    Liang D, Feng Y, Zandkarimi F, et al. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones[J]. Cell, 2023, 186(13): 2748–2764.e22. doi: 10.1016/j.cell.2023.05.003
    [68]
    Küch EM, Vellaramkalayil R, Zhang I, et al. Differentially localized acyl-CoA synthetase 4 isoenzymes mediate the metabolic channeling of fatty acids towards phosphatidylinositol[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2014, 1841(2): 227–239. doi: 10.1016/j.bbalip.2013.10.018
    [69]
    Doll S, Proneth B, Tyurina YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition[J]. Nat Chem Biol, 2017, 13(1): 91–98. doi: 10.1038/nchembio.2239
    [70]
    Kagan VE, Mao G, Qu F, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis[J]. Nat Chem Biol, 2017, 13(1): 81–90. doi: 10.1038/nchembio.2238
    [71]
    Zhang H, Hu B, Li Z, et al. PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis[J]. Nat cell Biol, 2022, 24(1): 88–98. doi: 10.1038/s41556-021-00818-3
    [72]
    Conrad M, Pratt DA. The chemical basis of ferroptosis[J]. Nat Chem Biol, 2019, 15(12): 1137–1147. doi: 10.1038/s41589-019-0408-1
    [73]
    Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease[J]. Nat Rev Mol Cell Biol, 2021, 22(4): 266–282. doi: 10.1038/s41580-020-00324-8
    [74]
    Singh NK, Rao GN. Emerging role of 12/15-Lipoxygenase (ALOX15) in human pathologies[J]. Prog Lipid Res, 2019, 73: 28–45. doi: 10.1016/j.plipres.2018.11.001
    [75]
    Wenzel S E, Tyurina Y Y, Zhao J, et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals[J]. Cell, 2017, 173(3): 628–641.e26. doi: 10.1016/j.cell.2017.09.044
    [76]
    Tschuck J, Theilacker L, Rothenaigner I, et al. Farnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis[J]. Nat Commun, 2023, 14(1): 6908. doi: 10.1038/s41467-023-42702-8
    [77]
    Ablasser A, Goldeck M, Cavlar T, et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING[J]. Nature, 2013, 498(7454): 380–384. doi: 10.1038/nature12306
    [78]
    Sun L, Wu J, Du F, et al. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway[J]. Science, 2013, 339(6121): 786–791. doi: 10.1126/science.1232458
    [79]
    Hopfner KP, Hornung V. Molecular mechanisms and cellular functions of cGAS–STING signalling[J]. Nat Rev Mol Cell Biol, 2020, 21(9): 501–521. doi: 10.1038/s41580-020-0244-x
    [80]
    Cheng Z, Dai T, He X, et al. The interactions between cGAS-STING pathway and pathogens[J]. Signal Transduct Target Ther, 2020, 5(1): 91. doi: 10.1038/s41392-020-0198-7
    [81]
    Jia M, Qin D, Zhao C, et al. Redox homeostasis maintained by GPX4 facilitates STING activation[J]. Nat Immunol, 2020, 21(7): 727–735. doi: 10.1038/s41590-020-0699-0
    [82]
    Li C, Liu J, Hou W, et al. STING1 promotes ferroptosis through MFN1/2-dependent mitochondrial fusion[J]. Front Cell Dev Biol, 2021, 9: 698679. doi: 10.3389/fcell.2021.698679
    [83]
    Santel A, Fuller MT. Control of mitochondrial morphology by a human mitofusin[J]. J Cell Sci, 2001, 114(5): 867–874. doi: 10.1242/jcs.114.5.867
    [84]
    Qiu S, Zhong X, Meng X, et al. Mitochondria-localized cGAS suppresses ferroptosis to promote cancer progression[J]. Cell Res, 2023, 33(4): 299–311. doi: 10.1038/s41422-023-00788-1
    [85]
    Fonseca TB, Sánchez-Guerrero Á, Milosevic I, et al. Mitochondrial fission requires DRP1 but not dynamins[J]. Nature, 2019, 570(7761): E34–E42. doi: 10.1038/s41586-019-1296-y
    [86]
    Wang W, Green M, Choi JE, et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy[J]. Nature, 2019, 569(7755): 270–274. doi: 10.1038/s41586-019-1170-y
    [87]
    Kong R, Wang N, Han W, et al. IFNγ-mediated repression of system xc drives vulnerability to induced ferroptosis in hepatocellular carcinoma cells[J]. J Leukoc Biol, 2021, 110(2): 301–314. doi: 10.1002/JLB.3MA1220-815RRR
    [88]
    Liau NPD, Laktyushin A, Lucet IS, et al. The molecular basis of JAK/STAT inhibition by SOCS1[J]. Nat Commun, 2018, 9(1): 1558. doi: 10.1038/s41467-018-04013-1
    [89]
    Saint-Germain E, Mignacca L, Vernier M, et al. SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes[J]. Aging (Albany NY), 2017, 9(10): 2137–2162. https://www.aging-us.com/article/101306/text
    [90]
    Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression[J]. Nature, 2015, 520(7545): 57–62. doi: 10.1038/nature14344
    [91]
    Chu B, Kon N, Chen D, et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway[J]. Nat Cell Biol, 2019, 21(5): 579–591. doi: 10.1038/s41556-019-0305-6
    [92]
    Dituri F, Mancarella S, Cigliano A, et al. TGF-β as multifaceted orchestrator in HCC progression: signaling, EMT, immune microenvironment, and novel therapeutic perspectives[J]. Semin Liver Dis, 2019, 39(1): 53–69. doi: 10.1055/s-0038-1676121
    [93]
    Bachman KE, Park BH. Duel nature of TGF-β signaling: tumor suppressor vs. tumor promoter[J]. Curr Opin Oncol, 2005, 17(1): 49–54. doi: 10.1097/01.cco.0000143682.45316.ae
    [94]
    Kim DH, Kim WD, Kim SK, et al. TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells[J]. Cell Death Dis, 2020, 11(5): 406. doi: 10.1038/s41419-020-2618-6
    [95]
    Pedrera L, Espiritu RA, Ros U, et al. Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics[J]. Cell Death Differ, 2021, 28(5): 1644–1657. doi: 10.1038/s41418-020-00691-x
    [96]
    Zhu Y, Zheng B, Wang H, et al. New knowledge of the mechanisms of sorafenib resistance in liver cancer[J]. Acta Pharmacol Sin, 2017, 38(5): 614–622. doi: 10.1038/aps.2017.5
    [97]
    Lee SY. Temozolomide resistance in glioblastoma multiforme[J]. Genes Dis, 2016, 3(3): 198–210. doi: 10.1016/j.gendis.2016.04.007
    [98]
    Sehm T, Rauh M, Wiendieck K, et al. Temozolomide toxicity operates in a xCT/SLC7a11 dependent manner and is fostered by ferroptosis[J]. Oncotarget, 2016, 7(46): 74630–74647. doi: 10.18632/oncotarget.11858
    [99]
    Koppula P, Zhang Y, Zhuang L, et al. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer[J]. Cancer Commun, 2018, 38(1): 12. doi: 10.1186/s40880-018-0288-x
    [100]
    Rohr-Udilova N, Bauer E, Timelthaler G, et al. Impact of glutathione peroxidase 4 on cell proliferation, angiogenesis and cytokine production in hepatocellular carcinoma[J]. Oncotarget, 2018, 9(11): 10054–10068. doi: 10.18632/oncotarget.24300
    [101]
    Chen H, Peng F, Xu J, et al. Increased expression of GPX4 promotes the tumorigenesis of thyroid cancer by inhibiting ferroptosis and predicts poor clinical outcomes[J]. Aging (Albany NY), 2023, 15(1): 230–245. https://www.aging-us.com/article/204473/text
    [102]
    Jones TD, Eble JN, Wang M, et al. Molecular genetic evidence for the independent origin of multifocal papillary tumors in patients with papillary renal cell carcinomas[J]. Clin Cancer Res, 2005, 11(20): 7226–7233. doi: 10.1158/1078-0432.CCR-04-2597
    [103]
    Xu F, Guan Y, Xue L, et al. The roles of ferroptosis regulatory gene SLC7A11 in renal cell carcinoma: a multi-omics study[J]. Cancer Med, 2021, 10(24): 9078–9096. doi: 10.1002/cam4.4395
    [104]
    Yu H, Han Z, Xu Z, et al. RNA sequencing uncovers the key long non-coding RNAs and potential molecular mechanism contributing to XAV939-mediated inhibition of non-small cell lung cancer[J]. Oncol Lett, 2019, 17(6): 4994–5004. doi: 10.3892/ol.2019.10191
    [105]
    Wu H, Liu A. Long non-coding RNA NEAT1 regulates ferroptosis sensitivity in non-small-cell lung cancer[J]. J Int Med Res, 2021, 49(3): 300060521996183. doi: 10.1177/0300060521996183
    [106]
    Rysman E, Brusselmans K, Scheys K, et al. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation[J]. Cancer Res, 2010, 70(20): 8117–8126. doi: 10.1158/0008-5472.CAN-09-3871
    [107]
    King ME, Yuan R, Chen J, et al. Long-chain polyunsaturated lipids associated with responsiveness to anti-PD-1 therapy are colocalized with immune infiltrates in the tumor microenvironment[J]. J Biol Chem, 2023, 299(3): 102902. doi: 10.1016/j.jbc.2023.102902
    [108]
    Liao P, Wang W, Wang W, et al. CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4[J]. Cancer Cell, 2022, 40(4): 365–378.e6. doi: 10.1016/j.ccell.2022.02.003
    [109]
    Xue Y, Lu F, Chang Z, et al. Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade[J]. Nat Commun, 2023, 14(1): 4758. doi: 10.1038/s41467-023-40518-0
    [110]
    Castellani RJ, Plascencia-Villa G, Perry G. The amyloid cascade and Alzheimer's disease therapeutics: theory versus observation[J]. Lab Invest, 2019, 99(7): 958–970. doi: 10.1038/s41374-019-0231-z
    [111]
    Butterfield DA, Boyd-Kimball D. Oxidative stress, amyloid-β peptide, and altered key molecular pathways in the pathogenesis and progression of Alzheimer's disease[J]. J Alzheimer's Dis, 2018, 62(3): 1345–1367. doi: 10.3233/JAD-170543
    [112]
    Galante D, Cavallo E, Perico A, et al. Effect of ferric citrate on amyloid-beta peptides behavior[J]. Biopolymers, 2018, 109(6): e23224. doi: 10.1002/bip.23224
    [113]
    Kalia LV, Lang AE. Parkinson's disease[J]. Lancet, 2015, 386(9996): 896–912. doi: 10.1016/S0140-6736(14)61393-3
    [114]
    Oñate M, Catenaccio A, Salvadores N, et al. The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease[J]. Cell Death Differ, 2020, 27(4): 1169–1185. doi: 10.1038/s41418-019-0408-4
    [115]
    Wang B, Ma Y, Li S, et al. GSDMD in peripheral myeloid cells regulates microglial immune training and neuroinflammation in Parkinson's disease[J]. Acta Pharm Sin B, 2023, 13(6): 2663–2679. doi: 10.1016/j.apsb.2023.04.008
    [116]
    Ward RJ, Zucca FA, Duyn JH, et al. The role of iron in brain ageing and neurodegenerative disorders[J]. Lancet Neurol, 2014, 13(10): 1045–1060. doi: 10.1016/S1474-4422(14)70117-6
    [117]
    Thomas GEC, Leyland LA, Schrag AE, et al. Brain iron deposition is linked with cognitive severity in Parkinson's disease[J]. J Neurol Neurosurg Psychiatry, 2020, 91(4): 418–425. doi: 10.1136/jnnp-2019-322042
    [118]
    Devos D, Moreau C, Devedjian JC, et al. Targeting chelatable iron as a therapeutic modality in Parkinson's disease[J]. Antioxid Redox Signal, 2014, 21(2): 195–210. doi: 10.1089/ars.2013.5593
    [119]
    Hu C, Nydes M, Shanley KL, et al. Reduced expression of the ferroptosis inhibitor glutathione peroxidase-4 in multiple sclerosis and experimental autoimmune encephalomyelitis[J]. J Neurochem, 2019, 148(3): 426–439. doi: 10.1111/jnc.14604
    [120]
    Baranovicova E, Kantorova E, Kalenska D, et al. Thalamic paramagnetic iron by T2* relaxometry correlates with severity of multiple sclerosis[J]. J Biomed Res, 2017, 31(4): 301–305. doi: 10.7555/JBR.31.20160023
    [121]
    Luoqian J, Yang W, Ding X, et al. Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis[J]. Cell Mol Immunol, 2022, 19(8): 913–924. doi: 10.1038/s41423-022-00883-0
    [122]
    Weiland A, Wang Y, Wu W, et al. Ferroptosis and its role in diverse brain diseases[J]. Mol Neurobiol, 2019, 56(7): 4880–4893. doi: 10.1007/s12035-018-1403-3
    [123]
    Skouta R, Dixon SJ, Wang J, et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models[J]. J Am Chem Soc, 2014, 136(12): 4551–4556. doi: 10.1021/ja411006a
    [124]
    Jiang Y, Ma C, Hu Y, et al. ECSIT is a critical factor for controlling intestinal homeostasis and tumorigenesis through regulating the translation of YAP protein[J]. Adv Sci, 2023, 10(25): 2205180. doi: 10.1002/advs.202205180
    [125]
    Garrett WS, Gordon JI, Glimcher LH. Homeostasis and inflammation in the intestine[J]. Cell, 2010, 140(6): 859–870. doi: 10.1016/j.cell.2010.01.023
    [126]
    Bourgonje AR, von Martels JZH, Bulthuis MLC, et al. Crohn's disease in clinical remission is marked by systemic oxidative stress[J]. Front Physiol, 2019, 10: 499. doi: 10.3389/fphys.2019.00499
    [127]
    Balmus IM, Ciobica A, Trifan A, et al. The implications of oxidative stress and antioxidant therapies in inflammatory bowel disease: clinical aspects and animal models[J]. Saudi J Gastroenterol, 2016, 22(1): 3–17. doi: 10.4103/1319-3767.173753
    [128]
    Banerjee P, Balraj P, Ambhore NS, et al. Network and co-expression analysis of airway smooth muscle cell transcriptome delineates potential gene signatures in asthma[J]. Sci Rep, 2021, 11(1): 14386. doi: 10.1038/s41598-021-93845-x
    [129]
    Zhao J, O'Donnell VB, Balzar S, et al. 15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells[J]. Proc Natl Acad Sci U S A, 2011, 108(34): 14246–14251. doi: 10.1073/pnas.1018075108
    [130]
    Wu Y, Chen H, Xuan N, et al. Induction of ferroptosis-like cell death of eosinophils exerts synergistic effects with glucocorticoids in allergic airway inflammation[J]. Thorax, 2020, 75(11): 918–927. doi: 10.1136/thoraxjnl-2020-214764
    [131]
    Chen Z, Wang W, Abdul Razak SR, et al. Ferroptosis as a potential target for cancer therapy[J]. Cell Death Dis, 2023, 14(7): 460. doi: 10.1038/s41419-023-05930-w
    [132]
    Huang K, Wei YH, Chiu YC, et al. Assessment of zero-valent iron-based nanotherapeutics for ferroptosis induction and resensitization strategy in cancer cells[J]. Biomater Sci, 2019, 7(4): 1311–1322. doi: 10.1039/C8BM01525B
    [133]
    Xu J, Zhang H, Zhang Y, et al. Controllable synthesis of variable-sized magnetic nanocrystals self-assembled into porous nanostructures for enhanced cancer chemo-ferroptosis therapy and MR imaging[J]. Nanoscale Adv, 2022, 4(3): 782–791. doi: 10.1039/D1NA00767J
    [134]
    Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4[J]. Cell, 2014, 156(1-2): 317–331. doi: 10.1016/j.cell.2013.12.010
    [135]
    Sui X, Zhang R, Liu S, et al. RSL3 drives ferroptosis through GPX4 inactivation and ROS production in colorectal cancer[J]. Front Pharmacol, 2018, 9: 1371. doi: 10.3389/fphar.2018.01371
    [136]
    Shimada K, Skouta R, Kaplan A, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis[J]. Nat Chem Biol, 2016, 12(7): 497–503. doi: 10.1038/nchembio.2079
    [137]
    Zhang X, Guo Y, Li H, et al. FIN56, a novel ferroptosis inducer, triggers lysosomal membrane permeabilization in a TFEB-dependent manner in glioblastoma[J]. J Cancer, 2021, 12(22): 6610–6619. doi: 10.7150/jca.58500
    [138]
    Zhao Y, Li Y, Zhang R, et al. The role of erastin in ferroptosis and its prospects in cancer therapy[J]. Onco Targets Ther, 2020, 13: 5429–5441. doi: 10.2147/OTT.S254995
    [139]
    Sato M, Kusumi R, Hamashima S, et al. The ferroptosis inducer erastin irreversibly inhibits system xc− and synergizes with cisplatin to increase cisplatin's cytotoxicity in cancer cells[J]. Sci Rep, 2018, 8(1): 968. doi: 10.1038/s41598-018-19213-4
    [140]
    Yamaguchi H, Hsu JL, Chen C, et al. Caspase-independent cell death is involved in the negative effect of EGF receptor inhibitors on cisplatin in non–small cell lung cancer cells[J]. Clin Cancer Res, 2013, 19(4): 845–854. doi: 10.1158/1078-0432.CCR-12-2621
    [141]
    Chen L, Li X, Liu L, et al. Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function[J]. Oncol Rep, 2015, 33(3): 1465–1474. doi: 10.3892/or.2015.3712
    [142]
    Lo M, Ling V, Low C, et al. Potential use of the anti-inflammatory drug, sulfasalazine, for targeted therapy of pancreatic cancer[J]. Curr Oncol, 2010, 17(3): 9–16. doi: 10.3747/co.v17i3.485
    [143]
    Tang X, Ding H, Liang M, et al. Curcumin induces ferroptosis in non-small-cell lung cancer via activating autophagy[J]. Thorac Cancer, 2021, 12(8): 1219–1230. doi: 10.1111/1759-7714.13904
    [144]
    Gai C, Yu M, Li Z, et al. Acetaminophen sensitizing erastin-induced ferroptosis via modulation of Nrf2/heme oxygenase-1 signaling pathway in non-small-cell lung cancer[J]. J Cell Physiol, 2020, 235(4): 3329–3339. doi: 10.1002/jcp.29221
    [145]
    Nakamura T, Hipp C, Santos Dias Mourão A, et al. Phase separation of FSP1 promotes ferroptosis[J]. Nature, 2023, 619(7969): 371–377. doi: 10.1038/s41586-023-06255-6
    [146]
    Chu J, Liu C, Song R, et al. Ferrostatin-1 protects HT-22 cells from oxidative toxicity[J]. Neural Regen Res, 2020, 15(3): 528. doi: 10.4103/1673-5374.266060
    [147]
    Sheng X, Shan C, Liu J, et al. Theoretical insights into the mechanism of ferroptosis suppression via inactivation of a lipid peroxide radical by liproxstatin-1[J]. Phys Chem Chem Phys, 2017, 19(20): 13153–13159. doi: 10.1039/C7CP00804J
    [148]
    Zilka O, Shah R, Li B, et al. On the mechanism of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death[J]. ACS Cent Sci, 2017, 3(3): 232–243. doi: 10.1021/acscentsci.7b00028
    [149]
    Deschamps JD, Kenyon VA, Holman TR. Baicalein is a potent in vitro inhibitor against both reticulocyte 15-human and platelet 12-human lipoxygenases[J]. Bioorg Med Chem, 2006, 14(12): 4295–4301. doi: 10.1016/j.bmc.2006.01.057
    [150]
    Gu X, Xu L, Liu Z, et al. The flavonoid baicalein rescues synaptic plasticity and memory deficits in a mouse model of Alzheimer's disease[J]. Behav Brain Res, 2016, 311: 309–321. doi: 10.1016/j.bbr.2016.05.052
    [151]
    Li Q, Li Q, Jia J, et al. Baicalein exerts neuroprotective effects in FeCl3-induced posttraumatic epileptic seizures via suppressing ferroptosis[J]. Front Pharmacol, 2019, 10: 638. doi: 10.3389/fphar.2019.00638
    [152]
    Wan Y, Shen K, Yu H, et al. Baicalein limits osteoarthritis development by inhibiting chondrocyte ferroptosis[J]. Free Radical Biol Med, 2023, 196: 108–120. doi: 10.1016/j.freeradbiomed.2023.01.006
    [153]
    Liu J, Zhou H, Chen J, et al. Baicalin inhibits IL-1β-induced ferroptosis in human osteoarthritis chondrocytes by activating Nrf-2 signaling pathway[J]. J Orthop Surg Res, 2024, 19(1): 23. doi: 10.1186/s13018-023-04483-0
    [154]
    Dang R, Wang M, Li X, et al. Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway[J]. J Neuroinflammation, 2022, 19(1): 41. doi: 10.1186/s12974-022-02400-6
    [155]
    Ni H, Song Y, Wu H, et al. 2-Methyl-5H-benzo [d] pyrazolo [5, 1-b][1, 3] oxazin-5-imine, an edaravone analog, exerts neuroprotective effects against acute ischemic injury via inhibiting oxidative stress[J]. J Biomed Res, 2018, 32(4): 270. doi: 10.7555/JBR.32.20180014
    [156]
    Li Y, Feng D, Wang Z, et al. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion[J]. Cell Death Differ, 2019, 26(11): 2284–2299. doi: 10.1038/s41418-019-0299-4
    [157]
    Li Q, Liao J, Chen W, et al. NAC alleviative ferroptosis in diabetic nephropathy via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2/Gpx4 pathway[J]. Free Radical Biol Med, 2022, 187: 158–170. doi: 10.1016/j.freeradbiomed.2022.05.024
    [158]
    Poggiali E, Cassinerio E, Zanaboni L, et al. An update on iron chelation therapy[J]. Blood Transfus, 2012, 10(4): 411–422. doi: 10.2450/2012.0008-12
    [159]
    Wu Y, Ran L, Yang Y, et al. Deferasirox alleviates DSS-induced ulcerative colitis in mice by inhibiting ferroptosis and improving intestinal microbiota[J]. Life Sci, 2023, 314: 121312. doi: 10.1016/j.lfs.2022.121312
    [160]
    Yao X, Zhang Y, Hao J, et al. Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis[J]. Neural Regen Res, 2019, 14(3): 532–541. doi: 10.4103/1673-5374.245480
    [161]
    Yang W, Mu B, You J, et al. Non-classical ferroptosis inhibition by a small molecule targeting PHB2[J]. Nat Commun, 2022, 13(1): 7473. doi: 10.1038/s41467-022-35294-2
    [162]
    Grootjans S, Vanden Berghe T, Vandenabeele P. Initiation and execution mechanisms of necroptosis: an overview[J]. Cell Death Differ, 2017, 24(7): 1184–1195. doi: 10.1038/cdd.2017.65
    [163]
    Cai Z, Jitkaew S, Zhao J, et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis[J]. Nat cell Biol, 2014, 16(1): 55–65. doi: 10.1038/ncb2883
    [164]
    Fadok VA, Voelker DR, Campbell PA, et al. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages[J]. J Immunol, 1992, 148(7): 2207–2216. doi: 10.4049/jimmunol.148.7.2207
    [165]
    Ellis RE, Yuan J, Horvitz HR. Mechanisms and functions of cell death[J]. Annu Rev Cell Biol, 1991, 7: 663–698. doi: 10.1146/annurev.cb.07.110191.003311
    [166]
    Chen X, He W, Hu L, et al. Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis[J]. Cell Res, 2016, 26(9): 1007–1020. doi: 10.1038/cr.2016.100
    [167]
    Liu X, Zhang Z, Ruan J, et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores[J]. Nature, 2016, 535(7610): 153–158. doi: 10.1038/nature18629
    [168]
    Edinger AL, Thompson CB. Death by design: apoptosis, necrosis and autophagy[J]. Curr Opin Cell Biol, 2004, 16(6): 663–669. doi: 10.1016/j.ceb.2004.09.011
  • Related Articles

    [1]Izzatullo Ziyoyiddin o`g`li Abdullaev, Ulugbek Gapparjanovich Gayibov, Sirojiddin Zoirovich Omonturdiev, Sobirova Fotima Azamjonovna, Sabina Narimanovna Gayibova, Takhir Fatikhovich Aripov. Molecular pathways in cardiovascular disease under hypoxia: Mechanisms, biomarkers, and therapeutic targets[J]. The Journal of Biomedical Research. DOI: 10.7555/JBR.38.20240387
    [2]Hongyan Li, Zhiyou Cai. SIRT3 regulates mitochondrial biogenesis in aging-related diseases[J]. The Journal of Biomedical Research, 2023, 37(2): 77-88. DOI: 10.7555/JBR.36.20220078
    [3]Xiao Min, Xue Yi, Wu Zhongzhi, Lei Zi-Ning, Wang Jin, Chen Zhe-Sheng, Li Wei. Design, synthesis and biological evaluation of selective survivin inhibitors[J]. The Journal of Biomedical Research, 2019, 33(2): 82-100. DOI: 10.7555/JBR.31.20160173
    [4]Huan Liu, Shijiang Zhang, Yongfeng Shao, Xiaohu Lu, Weidong Gu, Buqing Ni, Qun Gu, Junjie Du. Biomechanical characterization of a novel ring connector for sutureless aortic anastomosis[J]. The Journal of Biomedical Research, 2018, 32(6): 454-460. DOI: 10.7555/JBR.31.20170011
    [5]Fengzhen Wang, Mingwan Zhang, Dongsheng Zhang, Yuan Huang, Li Chen, Sunmin Jiang, Kun Shi, Rui Li. Preparation, optimization, and characterization of chitosancoated solid lipid nanoparticles for ocular drug delivery[J]. The Journal of Biomedical Research, 2018, 32(6): 411-423. DOI: 10.7555/JBR.32.20160170
    [6]Eika S. Webb, Peng Liu, Renato Baleeiro, Nicholas R. Lemoine, Ming Yuan, Yaohe Wang. Immune checkpoint inhibitors in cancer therapy[J]. The Journal of Biomedical Research, 2018, 32(5): 317-326. DOI: 10.7555/JBR.31.20160168
    [7]Di Zhao, Ze-Mu Wang, Lian-Sheng Wang. Prevention of atrial fibrillation with renin-angiotensin system inhibitors on essential hypertensive patients: a meta-analysis of randomized controlled trials[J]. The Journal of Biomedical Research, 2015, 29(6): 475-485. DOI: 10.7555/JBR.29.20140149
    [8]Ye Bi, Mingxi Liu, Wenjiao Tu, Yibo Wu, Xuejiang Guo, Zuomin Zhou, Jiahao Sha. The expression and localization of a novel protein phosphatase inhibitor 2810408A11Rik in mouse testis and sperm[J]. The Journal of Biomedical Research, 2012, 26(2): 110-116. DOI: 10.1016/S1674-8301(12)60020-7
    [9]Sundeep?S.?Tumber, Hong?Liu. Epidural abscess after multiple lumbar punctures for labour epidural catheter placement[J]. The Journal of Biomedical Research, 2010, 24(4): 332-335. DOI: 10.1016/S1674-8301(10)60046-2
    [10]Hongbing Zhang, Naixue Sun, Houcheng Liang, Xianghua Xiao, Xianning Liu, Yani Wang. The protective effect of 17 beta-estradiol on oxygen-induced retinopathy and its relation with the changes of malondialdehyde[J]. The Journal of Biomedical Research, 2010, 24(2): 138-144.

Catalog

    Figures(3)  /  Tables(2)

    Article Metrics

    Article views (678) PDF downloads (274) Cited by()
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return