The emerging role and therapeutical implications of ferroptosis in wound healing

Abstract

Wound healing is a complex biological process involving multiple steps, including hemostasis, inflammation, proliferation, and remodeling. A novel form of regulated cell death, ferroptosis, has garnered attention because of its involvement in these processes. Ferroptosis is characterized by the accumulation of lipid peroxides and is tightly regulated by lipid metabolism, iron metabolism, and the lipid-peroxide repair network, all of which exert a significant influence on wound healing. This review highlights the current findings and emerging concepts regarding the multifaceted roles of ferroptosis throughout the stages of normal and chronic wound healing. Additionally, the potential of targeted interventions aimed at modulating ferroptosis to improve wound-healing outcomes is discussed.

Keywords

Wound healing / Ferroptosis / Iron / Lipid peroxidation / Therapies

References

[1] Almadani YH, Vorstenbosch J, Davison PG, Murphy AM. Wound healing: a comprehensive review. Semin Plast Surg 2021; 35: 141-4. https://doi.org/10.1055/s-0041-1731791.

[2] Stockwell BR. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell 2022; 185: 2401-21. https://doi.org/10.1016/j.cell.2022.06.003.

[3] Bi M, Li D, Zhang J. Research progress and insights on the role of ferroptosis in wound healing. Int Wound J 2023; 20: 2473-81. https://doi.org/10.1111/iwj.14102.

[4] Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149: 1060-72. https://doi.org/10.1016/j.cell.2012.03.042.

[5] Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X. et al. Ferroptosis: process and function. Cell Death Differ 2016; 23: 369-79. https://doi.org/10.1038/cdd.2015.158.

[6] Stockwell BR, Jiang X. The chemistry and biology of Ferroptosis. Cell Chem Biol 2020; 27: 365-75. https://doi.org/10.1016/j.chembiol.2020.03.013.

[7] Conrad M, Pratt DA. The chemical basis of ferroptosis. Nat Chem Biol 2019; 15: 1137-47. https://doi.org/10.1038/s41589-019-0408-1.

[8] Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 2017; 13: 91-8. https://doi.org/10.1038/nchembio.2239.

[9] Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 2017; 13: 81-90. https://doi.org/10.1038/nchembio.2238.

[10] Reed A, Ichu TA, Milosevich N, Melillo B, Schafroth MA, Otsuka Y. et al. LPCAT3 inhibitors remodel the polyunsaturated phospholipid content of human cells and protect from Ferroptosis. ACS Chem Biol 2022; 17: 1607-18. https://doi.org/10.1021/acscchembio.2c00317.

[11] Zhang HL, Hu BX, Li ZL, Du T, Shan JL, Ye ZP. et al. PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat Cell Biol 2022; 24: 88-98. https://doi.org/10.1038/s41556-021-00818-3.

[12] Magtanong L, Ko PJ, To M, Cao JY, Forcina GC, Tarangelo A. et al. Exogenous monounsaturated fatty acids promote a Ferroptosis-resistant cell state. Cell Chem Biol 2019; 26: 420-432.e9. https://doi.org/10.1016/j.chembiol.2018.11.016.

[13] Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA 2016; 113: E4966-75. https://doi.org/10.1073/pnas.1603244113.

[14] Zou Y, Henry WS, Ricq EL, Graham ET, Phadnis VV, Maretich P. et al. Plasticity of ether lipids promotes ferroptosis susceptibility and evasion. Nature 2020; 585: 603-8. https://doi.org/10.1038/s41586-020-2732-8.

[15] Liang D, Feng Y, Zandkarimi F, Wang H, Zhang Z, Kim J. et al. Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones. Cell 2023; 186: 2748-64.e22. https://doi.org/10.1016/j.cell.2023.05.003.

[16] Zou Y, Li H, Graham ET, Deik AA, Eaton JK, Wang W. et al. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat Chem Biol 2020; 16: 302-9. https://doi.org/10.1038/s41589-020-0472-6.

[17] Yan B, Ai Y, Sun Q, Ma Y, Cao Y, Wang J. et al. Membrane damage during Ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol Cell 2021; 81: 355-69.e10. https://doi.org/10.1016/j.molcel.2020.11.024.

[18] Galy B, Conrad M, Muckenthaler M. Mechanisms controlling cellular and systemic iron homeostasis. Nat Rev Mol Cell Biol 2024; 25: 133-55. https://doi.org/10.1038/s41580-023-00648-1.

[19] Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ, 3rd. et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 2016; 12: 1425-8. https://doi.org/10.1080/15548627.2016.1187366.

[20] Fang X, Wang H, Han D, Xie E, Yang X, Wei J. et al. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci USA 2019; 116: 2672-80. https://doi.org/10.1073/pnas.1821022116.

[21] Yi W, Zhang J, Huang Y, Zhan Q, Zou M, Cheng X. et al. Ferritin-mediated mitochondrial iron homeostasis is essential for the survival of hematopoietic stem cells and leukemic stem cells. Leukemia 2024; 38: 1003-18. https://doi.org/10.1038/s41375-024-02169-y.

[22] Zhang F, Li K, Zhang W, Zhao Z, Chang F, Du J. et al. Ganglioside GM3 protects against abdominal aortic aneurysm by suppressing Ferroptosis. Circulation 2024; 149: 843-59. https://doi.org/10.1161/CIRCULATIONAHA.123.066110.

[23] Chen G-Q, Benthani FA, Wu J, Liang D, Bian Z-X, Jiang X. Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis. Cell Death Differ 2020; 27: 242-54. https://doi.org/10.1038/s41418-019-0352-3.

[24] Dixon SJ, Olzmann JA. The cell biology of ferroptosis. Nat Rev Mol Cell Biol 2024; 25: 424-42. https://doi.org/10.1038/s41580-024-00703-5.

[25] Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156: 317-31. https://doi.org/10.1016/j.cell.2013.12.010.

[26] Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 2014; 16: 1180-91. https://doi.org/10.1038/ncb3064.

[27] Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 2019; 575: 693-8. https://doi.org/10.1038/s41586-019-1707-0.

[28] Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 2019; 575: 688-92. https://doi.org/10.1038/s41586-019-1705-2.

[29] Mishima E, Ito J, Wu Z, Nakamura T, Wahida A, Doll S. et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 2022; 608: 778-83. https://doi.org/10.1038/s41586-022-05022-3.

[30] Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 2021; 22: 266-82. https://doi.org/10.1038/s41580-020-00324-8.

[31] Nakamura T, Hipp C, Santos Dias Mourão A, Borggräfe J, Aldrovandi M, Henkelmann B. et al. Phase separation of FSP1 promotes ferroptosis. Nature 2023; 619: 371-7. https://doi.org/10.1038/s41586-023-06255-6.

[32] Kraft VAN, Bezjian CT, Pfeiffer S, Ringelstetter L, Muller C, Zandkarimi F. et al. GTP Cyclohydrolase 1/tetrahydrobiopterin counteract Ferroptosis through lipid Remodeling. ACS Cent Sci 2020; 6: 41-53. https://doi.org/10.1021/acscentsci.9b01063.

[33] Mao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H. et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 2021; 593: 586-90. https://doi.org/10.1038/s41586-021-03539-7.

[34] Li Y, Ran Q, Duan Q, Jin J, Wang Y, Yu L. et al. 7-Dehydrocholesterol dictates ferroptosis sensitivity. Nature 2024; 626: 411-8. https://doi.org/10.1038/s41586-023-06983-9.

[35] Freitas FP, Alborzinia H, Dos Santos AF, Nepachalovich P, Pedrera L, Zilka O. et al. 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis. Nature 2024; 626: 401-10. https://doi.org/10.1038/s41586-023-06878-9.

[36] Zhang J, Su T, Fan Y, Cheng C, Xu L, Li Tian. Spotlight on iron overload and ferroptosis: research progress in female infertility. Life Sci 2024; 340: 122370. https://doi.org/10.1016/j.lfs.2023.122370.

[37] Ou M, Jiang Y, Ji Y, Zhou Q, Du Z, Zhu H. et al. Role and mechanism of ferroptosis in neurological diseases. Mol Metab 2022; 61: 101502. https://doi.org/10.1016/j.molmet.2022.101502.

[38] Tsurusaki S, Tsuchiya Y, Koumura T, Nakasone M, Sakamoto T, Matsuoka M. et al. Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis. Cell Death Dis 2019; 10: 449. https://doi.org/10.1038/s41419-019-1678-y.

[39] Park E-J, Park Y-J, Lee SJ, Lee K, Yoon C. Whole cigarette smoke condensates induce ferroptosis in human bronchial epithelial cells. Toxicol Lett 2019; 303: 55-66. https://doi.org/10.1016/j.toxlet.2018.12.007.

[40] Yao Y, Chen Z, Zhang H, Chen C, Zeng M, Yunis J. et al. Selenium-GPX4 axis protects follicular helper T cells from ferroptosis. Nat Immunol 2021; 22: 1127-39. https://doi.org/10.1038/s41590-021-00996-0.

[41] Liao P, Wang W, Wang W, Kryczek I, Li X, Bian Y. et al. CD8(+) T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell 2022; 40: 365-78. https://doi.org/10.1016/j.ccell.2022.02.003.

[42] Shen QA-O, Liang MA-O, Yang FA-O, Deng YA-O, Naqvi NA-O. Ferroptosis contributes to developmental cell death in rice blast. New Phytol 2020; 227: 1831-46. https://doi.org/10.1111/nph.16636.

[43] Co HA-O, Wu CC, Lee YC, Chen SA-O. Emergence of large-scale cell death through ferroptotic trigger waves. Nature 2024; 631: 654-62. https://doi.org/10.1038/s41586-024-07623-6.

[44] Jenkins NL, James SA, Salim A, Sumardy F, Speed TP, Conrad M. et al. Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging Caenorhabditis elegans. Elife 2020; 9: e56580. https://doi.org/10.7554.

[45] Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound healing: a cellular perspective. Physiol Rev 2019; 99: 665-706. https://doi.org/10.1152/physrev.00067.2017.

[46] Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med 2014; 6: 265sr6. https://doi.org/10.1126/scitranslmed.3009337.

[47] Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen 2008; 16: 585-601. https://doi.org/10.1111/j.1524-475X.2008.00410.x.

[48] Kattula S, Byrnes JR, Wolberg AS. Fibrinogen and fibrin in Hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 2017; 37: E13-21. https://doi.org/10.1161/ATVBAHA.117.308564.

[49] Luo L, Zhang H, Zhang S, Luo C, Kan X, Lv J. et al. Extracellular vesicle-derived silk fibroin nanoparticles loaded with MFGE8 accelerate skin ulcer healing by targeting the vascular endothelial cells. J Nanobiotechnology 2023; 21: 455. https://doi.org/10.1186/s12951-023-02185-7.

[50] Lu W, Li XY, Wang ZY, Zhao CB, Li Q, Zhang L. et al. Mesenchymal stem cell-derived extracellular vesicles accelerate diabetic wound healing by inhibiting NET-induced ferroptosis of endothelial cells. Int J Biol Sci 2024; 20: 3515-29. https://doi.org/10.7150/ijbs.97150.

[51] Zhou DL, Liang Q, Ge XY, Xu J. Allogeneic platelet-rich plasma inhibits ferroptosis in promoting wound repair of type 2 diabetic ulcers. Free Radic Biol Med 2024; 215: 37-47. https://doi.org/10.1016/j.freeradbiomed.2024.02.020.

[52] Long T, Li C, Xu F, Xiao J. Therapeutic efficacy of platelet-rich fibrin on surgical site wound healing in patients undergoing oral carcinoma resection: a meta-analysis. Int Wound J 2024; 21: e14386. https://doi.org/10.1111/iwj.14386.

[53] Ibne Mahbub MS, Bae SH, Gwon JG, Lee BT, Strukova SM, Dugina Tn Fau-Chistov IV. et al. Decellularized liver extracellular matrix and thrombin loaded biodegradable TOCN/chitosan nanocomposite for hemostasis and wound healing in rat liver hemorrhage model immobilized thrombin receptor agonist peptide accelerates wound healing in mice. Int J Biol Macromol 2023; 225: 1529-42. https://doi.org/10.1016/j.ijbiomac.202.

[54] Strukova SM, Dugina TN, Chistov IV, Lange M, Markvicheva EA, Kuptsova S. et al. Immobilized thrombin receptor agonist peptide accelerates wound healing in mice. Clin Appl Thromb Hemost 2001; 7: 325-9. https://doi.org/10.1177/107602960100700414.

[55] Gugerell A, Pasteiner W, Nürnberger S, Kober J, Meinl A, Pfeifer S. et al. Thrombin as important factor for cutaneous wound healing: comparison of fibrin biomatrices in vitro and in a rat excisional wound healing model. Wound Repair Regen 2014; 22: 740-8. https://doi.org/10.1111/wrr.12234.

[56] Xu S, Tuo QZ, Meng J, Wu XL, Li CL, Lei P. Thrombin induces ferroptosis in triple-negative breast cancer through the cPLA2α/ACSL4 signaling pathway. Transl Oncol 2024; 39: 101817. https://doi.org/10.1016/j.trano.

[57] Tuo QZ, Liu Y, Xiang Z, Yan HF, Zou T, Shu Y. et al. Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion. Signal Transduct Target Ther 2022; 7: 59. https://doi.org/10.1038/s41392-022-00917-z.

[58] NaveenKumar SK, SharathBabu BN, Hemshekhar M, Kemparaju K, Girish KS, Mugesh G. The role of reactive oxygen species and Ferroptosis in Heme-mediated activation of human platelets. ACS Chem Biol 2018; 13: 1996-2002. https://doi.org/10.1021/acschembio.8b00458.

[59] Krzyszczyk P, Schloss R, Palmer A, Berthiaume F. The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front Physiol 2018; 9: 419. https://doi.org/10.3389/fphys.2018.00419.

[60] Soliman AM, Barreda DR. Acute inflammation in tissue healing. Int J Mol Sci 2022; 24: 641. https://doi.org/10.3390/ijms24010641.

[61] Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 2007; 127: 514-25. https://doi.org/10.1038/sj.jid.5700701.

[62] Medrado AR, Pugliese LS, Reis SR, Andrade ZA. Influence of low level laser therapy on wound healing and its biological action upon myofibroblasts. Lasers Surg Med 2003; 32: 239-44. https://doi.org/10.1002/lsm.10126.

[63] Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB.Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 2014; 20: 1126-67. https://doi.org/10.1089/ars.2012.5149.

[64] Chen L, Xiong S, She H, Lin SW, Wang J, Tsukamoto H. Iron causes interactions of TAK1, p21ras, and phosphatidylinositol 3-kinase in caveolae to activate IkappaB kinase in hepatic macrophages. J Biol Chem 2007; 282: 5582-8. https://doi.org/10.1074/jbc.M609273200.

[65] Xiong S, She H, Takeuchi H, Han B, Engelhardt JF, Barton CH. et al. Signaling role of intracellular iron in NF-kappaB activation. J Biol Chem 2003; 278: 17646-54. https://doi.org/10.1074/jbc.M210905200.

[66] Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H. et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest 2011; 121: 985-97. https://doi.org/10.1172/JCI44490.

[67] Zhou Y, Que KT, Zhang Z, Yi ZJ, Zhao PX, You Y. et al. Iron overloaded polarizes macrophage to proinflammation phenotype through ROS/acetyl-p53 pathway. Cancer Med 2018; 7: 4012-22. https://doi.org/10.1002/cam4.1670.

[68] Kroner A, Greenhalgh AD, Zarruk JG, Passos Dos Santos R, Gaestel M, David S. TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron 2014; 83: 1098-116. https://doi.org/10.1016/j.neuron.2014.0.

[69] Mohammadpour M, Behjati M, Sadeghi A, Fassihi A. Wound healing by topical application of antioxidant iron chelators: kojic acid and deferiprone. Int Wound J 2013; 10: 260-4. https://doi.org/10.1111/j.1742-481X.2012.00971.x.

[70] Guo J, Peng J, Han J, Wang K, Si R, Shan H. et al. Extracts of Portulaca oleracea promote wound healing by enhancing angiology regeneration and inhibiting iron accumulation in mice. Chin Herb Med 2022; 14: 263-72. https://doi.org/10.1016/j.chmed.2021.09.014.

[71] Qin W, Liu K, Su H, Hou J, Yang S, Pan K. et al. Tibial cortex transverse transport promotes ischemic diabetic foot ulcer healing via enhanced angiogenesis and inflammation modulation in a novel rat model. Eur J Med Res 2024; 29: 155. https://doi.org/10.1186/s40001-024-01752-4.

[72] Falanga V, Isseroff RR, Soulika AM, Romanelli M, Margolis D, Kapp S. et al. Chronic wounds. Nat Rev Dis Primers 2022; 8: 50. https://doi.org/10.1038/s41572-022-00377-3.

[73] McDermott K, Fang M, Boulton AJM, Selvin E, Hicks CW. Etiology, epidemiology, and disparities in the burden of diabetic foot ulcers. Diabetes Care 2023; 46: 209-21. https://doi.org/10.2337/dci22-0043.

[74] Harrison AV, Lorenzo FR, McClain DA. Iron and the pathophysiology of diabetes. Annu Rev Physiol 2023; 85: 339-62. https://doi.org/10.1146/annurev-physiol-022522-102832.

[75] Qasim N, Arif A, Mahmood R. Hyperglycemia enhances the generation of ROS and RNS that impair antioxidant power and cause oxidative damage in human erythrocytes. Biochem Cell Biol 2022; 101: 64-76. https://doi.org/10.1139/bcb-2022-0008.

[76] Volpe CMO, Villar-Delfino PH, dos Anjos PMF, Nogueira-Machado JA. Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death Dis 2018; 9: 119. https://doi.org/10.1038/s41419-017-0135-z.

[77] Duscher D, Neofytou E, Wong VW, Maan ZN, Rennert RC, Inayathullah M. et al. Transdermal deferoxamine prevents pressure-induced diabetic ulcers. Proc Natl Acad Sci 2015; 112: 94-9. https://doi.org/10.1073/pnas.1413445112.

[78] Chen H, Jia P, Kang H, Zhang H, Liu Y, Yang P. et al. Upregulating Hif-1α by hydrogel Nanofibrous scaffolds for rapidly recruiting angiogenesis relative cells in diabetic wound. Adv Healthc Mater 2016; 5: 907-18. https://doi.org/10.1002/adhm.201501018.

[79] Cui S, Liu X, Liu Y, Hu W, Ma K, Huang Q. et al. Autophagosomes defeat Ferroptosis by decreasing generation and increasing discharge of free Fe²⁺ in skin repair cells to accelerate diabetic wound healing. Adv Sci 2023; 10: e2300414. https://doi.org/10.1002/advs.202300414.

[80] Li S, Li Y, Wu Z, Wu Z, Fang H. Diabetic ferroptosis plays an important role in triggering on inflammation in diabetic wound. Am J Physiol Endocrinol Metab 2021; 321: E509-20. https://doi.org/10.1152/ajpendo.00042.2021.

[81] Wang T, Zheng Y, Zhang J, Wu Z. Targeting ferroptosis promotes diabetic wound healing via Nrf2 activation. Heliyon 2024; 10: e37477. https://doi.org/10.1016/j.heliyon.2024.e37477.

[82] Yang X, Ren H, Guo X, Hu C, Fu J. Radiation-induced skin injury: pathogenesis, treatment, and management. Aging 2020; 12: 23379-93. https://doi.org/10.18632/aging.103932.

[83] Ye LF, Chaudhary KR, Zandkarimi F, Harken AD, Kinslow CJ, Upadhyayula PS. et al. Radiation-induced lipid peroxidation triggers Ferroptosis and synergizes with Ferroptosis inducers. ACS Chem Biol 2020; 15: 469-84. https://doi.org/10.1021/acschembio.9b00939.

[84] Lei G, Zhang Y, Koppula P, Liu X, Zhang J, Lin SH. et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res 2020; 30: 146-62. https://doi.org/10.1038/s41422-019-0263-3.

[85] Li X, Zhuang X, Qiao T. Role of ferroptosis in the process of acute radiation-induced lung injury in mice. Biochem Biophys Res Commun 2019; 519: 240-5. https://doi.org/10.1016/j.bbrc.2019.08.165.

[86] Thermozier S, Hou W, Zhang X, Shields D, Fisher R, Bayir H. et al. Anti-Ferroptosis drug enhances Total-body irradiation mitigation by drugs that block apoptosis and necroptosis. Radiat Res 2020; 193: 435-50. https://doi.org/10.1667/RR15486.1.

[87] Zhang X, Xing X, Liu H, Feng J, Tian M, Chang S. et al. Ionizing radiation induces ferroptosis in granulocyte-macrophage hematopoietic progenitor cells of murine bone marrow. Int J Radiat Biol 2020; 96: 584-95. https://doi.org/10.1080/09553002.2020.1708993.

[88] Vats K, Kruglov O, Mizes A, Samovich SN, Amoscato AA, Tyurin VA. et al. Keratinocyte death by ferroptosis initiates skin inflammation after UVB exposure. Redox Biol 2021; 47: 102143. https://doi.org/10.1016/j.redox.2021.102143.

[89] Feng Z, Qin Y, Huo F, Jian Z, Li X, Geng J. et al. NMN recruits GSH to enhance GPX4-mediated ferroptosis defense in UV irradiation induced skin injury. Biochim Biophys Acta (BBA)-Mol Basis Dis 2022; 1868: 166287. https://doi.org/10.1016/j.bbadis.2021.166287.

[90] Nasir NJM, Heemskerk H, Jenkins J, Hamadee NH, Bunte R, Tucker-Kellogg L. Myoglobin-derived iron causes wound enlargement and impaired regeneration in pressure injuries of muscle. elife 2023; 12: 12. https://doi.org/10.7554/eLife.85633.

[91] Ishikawa M, Uchiyama A, Kosaka K, Nishio M, Ogino S, Yokoyama Y. et al. Exposure to volatile ferroptosis inhibitor, TEMPO, reduced cutaneous ischemia-reperfusion injury progression to pressure ulcer formation in a mouse model. J Dermatol Sci 2024; 115: 130-40. https://doi.org/10.1016/j.jdermsci.2024.07.005.

[92] Caggiati A, Rosi C, Casini A, Cirenza M, Petrozza V, Acconcia MC. et al. Skin iron deposition characterises lipodermatosclerosis and leg ulcer. Eur J Vasc Endovasc Surg 2010; 40: 777-82. https://doi.org/10.1016/j.ejvs.2010.08.015.

[93] Wenk J, Foitzik A, Achterberg V, Sabiwalsky A, Dissemond J, Meewes C. et al. Selective pick-up of increased iron by deferoxamine-coupled cellulose abrogates the iron-driven induction of matrix-degrading metalloproteinase 1 and lipid peroxidation in human dermal fibroblasts in vitro: a new dressing concept. J Invest Dermatol 2001; 116: 833-9. https://doi.org/10.1046/j.1523-1747.2001.01345.x.

[94] Yeoh-Ellerton S, Stacey MC. Iron and 8-isoprostane levels in acute and chronic wounds. J Invest Dermatol 2003; 121: 918-25. https://doi.org/10.1046/j.1523-1747.2003.12471.x.

[95] Yao X, Zhang Y, Hao J, Duan HQ, Zhao CX, Sun C. et al. Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis. Neural Regen Res 2019; 14: 532-41. https://doi.org/10.4103/1673-5374.245480.

[96] Bao Z, Liu Y, Chen B, Miao Z, Tu Y, Li C, et al. Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury. Nat Commun 2021; 12: 4220. https://doi.org/10.1038/s41467-021-24469-y.

[97] Li QS, Jia YJ. Ferroptosis: a critical player and potential therapeutic target in traumatic brain injury and spinal cord injury. Neural Regen Res 2023;18:506-12. https://doi.org/10.4103/1673-5374.350187.

[98] Fang J, Yuan Q, Du Z, Zhang Q, Yang L, Wang M. et al. Overexpression of GPX4 attenuates cognitive dysfunction through inhibiting hippocampus ferroptosis and neuroinflammation after traumatic brain injury. Free Radic Biol Med 2023; 204: 68-81. https://doi.org/10.1016/j.freeradbiomed.2023.04.014.

[99] Xie B-S, Wang Y-Q, Lin Y, Mao Q, Feng J-F, Gao G-Y. et al. Inhibition of ferroptosis attenuates tissue damage and improves long-term outcomes after traumatic brain injury in mice. CNS Neurosci Ther 2019; 25: 465-75. https://doi.org/10.1111/cns.13069.

[100] Pastar I, Stojadinovic O, Yin NC, Ramirez H, Nusbaum AG, Sawaya A. et al. Epithelialization in wound healing: a comprehensive review. Adv Wound Care 2014; 3: 445-64. https://doi.org/10.1089/wound.2013.0473.

[101] Al, Sadoun H. Macrophage phenotypes in normal and diabetic wound healing and therapeutic interventions. Cells 2022; 11: 2430. https://doi.org/10.3390/cells11152430.

[102] Cheng H, Huang H, Guo Z, Chang Y, Li Z. Role of prostaglandin E2 in tissue repair and regeneration. Theranostics 2021; 11: 8836-54. https://doi.org/10.7150/thno.63396.

[103] Zhang S, Liu Y, Zhang X, Zhu D, Qi X, Cao X. et al. Prostaglandin E(2) hydrogel improves cutaneous wound healing via M2 macrophages polarization. Theranostics 2018; 8: 5348-61. https://doi.org/10.7150/thno.27385.

[104] Xu Y, Liu Y, Li K, Yuan D, Yang S, Zhou L. et al. COX-2/PGE2 pathway inhibits the Ferroptosis induced by cerebral ischemia reperfusion. Mol Neurobiol 2022; 59: 1619-31. https://doi.org/10.1007/s12035-021-02706-1.

[105] Wang B, Jin Y, Liu J, Liu Q, Shen Y, Zuo S. et al. EP1 activation inhibits doxorubicin-cardiomyocyte ferroptosis via Nrf2. Redox Biol 2023; 65: 102825. https://doi.org/10.1016/j.redox.2023.102825.

[106] DiPietro LA. Angiogenesis and wound repair: when enough is enough. J Leukoc Biol 2016; 100: 979-84. https://doi.org/10.1189/jlb.4MR0316-102R.

[107] Cao G, Yin S, Ma J, Lu Y, Song R, Wu Z. et al. YAP promotes the healing of ischemic wounds by reducing ferroptosis in skin fibroblasts through inhibition of ferritinophagy. Heliyon 2024; 10:e24602. https://doi.org/10.1016/j.heliyon.2024.e24602.

[108] Luo EF, Li HX, Qin YH, Qiao Y, Yan GL, Yao YY. et al. Role of ferroptosis in the process of diabetes-induced endothelial dysfunction. World J Diabetes 2021; 12: 124-37. https://doi.org/10.4239/wjd.v12.i2.124.

[109] Pasaribu KM, Ilyas S, Tamrin T, Radecka I, Swingler S, Gupta A. et al. Bioactive bacterial cellulose wound dressings for burns with collagen in-situ and chitosan ex-situ impregnation. Int J Biol Macromol 2023; 230: 123118. https://doi.org/10.1016/j.ijbiomac.2022.123118.

[110] Broughton G, 2nd, Janis JE, Attinger CE. Wound healing: an overview. Plast Reconstr Surg 2006; 117: 1e-32e-S. https://doi.org/10.1097/01.prs.0000222562.60260.f9.

[111] Velnar T, Bailey T, Smrkolj V. The wound healing process: an overview of the cellular and molecular mechanisms. J Int Med Res 2009; 37: 1528-42. https://doi.org/10.1177/147323000903700531.

[112] Gonzalez AC, Costa TF, Andrade ZA, Medrado AR. Wound healing-a literature review. An Bras Dermatol 2016; 91: 614-20. https://doi.org/10.1590/abd1806-4841.20164741.

[113] Ezzo M, Hinz B. Novel approaches to target fibroblast mechanotransduction in fibroproliferative diseases. Pharmacol Ther 2023; 250: 108528. https://doi.org/10.1016/j.pharmthera.2023.108528.

[114] Schuster R, Younesi F, Ezzo M, Hinz B. The role of Myofibroblasts in physiological and pathological tissue repair. Cold Spring Harb Perspect Biol 2023; 15:a041231. https://doi.org/10.1101/cshperspect.a041231.

[115] Tian H, Li S, Jia W, Yu K, Wu G. Risk factors for poor hemostasis of prophylactic uterine artery embolization before curettage in cesarean scar pregnancy. J Int Med Res 2020; 48: 300060520964379. https://doi.org/10.1177/0300060520964379.

[116] Yuan T, Meijia L, Rong C, Jian Y, Lijun H. Identification of novel biomarkers of ferroptosis involved in keloid based on bioinformatics analysis. Int Wound J 2024; 21: e14606. https://doi.org/10.1111/iwj.14606.

[117] Zhang J, Liu L, Li X, Shen X, Yang G, Deng Y. et al. 5-ALA-PDT induced ferroptosis in keloid fibroblasts via ROS, accompanied by downregulation of xCT, GPX4. Photodiagn Photodyn Ther 2023; 42: 103612. https://doi.org/10.1016/j.pdpdt.2023.103612.

[118] Yang L, Li X, Wang Y. Ferrostatin-1 inhibits fibroblast fibrosis in keloid by inhibiting ferroptosis. PeerJ 2024; 12: e17551. https://doi.org/10.7717/peerj.17551.

[119] Recalcati S, Gammella E, Buratti P, Doni A, Anselmo A, Locati M. et al. Macrophage ferroportin is essential for stromal cell proliferation in wound healing. Haematologica 2019; 104: 47-58. https://doi.org/10.3324/haematol.2018.197517.

[120] Wang H, An P, Xie EJ, Wu Q, Fang XX, Gao H. et al. Characterization of ferroptosis in murine models of hemochromatosis. Hepatology 2017; 66: 449-65. https://doi.org/10.1002/hep.29117.

[121] Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K. et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc 2014; 136: 4551-6. https://doi.org/10.1021/ja411006a.

[122] Hofmans S, Berghe TV, Devisscher L, Hassannia B, Lyssens S, Joossens J. et al. Novel Ferroptosis inhibitors with improved potency and ADME properties. J Med Chem 2016; 59: 2041-53. https://doi.org/10.1021/acs.jmedchem.5b01641.

[123] Mizuno H, Kubota C, Takigawa Y, Shintoku R, Kannari N, Muraoka T. et al. 2,2,6,6-Tetramethylpiperidine-1-oxyl acts as a volatile inhibitor of ferroptosis and neurological injury. J Biochem 2022; 172: 71-8. https://doi.org/10.1093/jb/mvac044.

[124] Zilka O, Poon J-F, Pratt DA. Radical-trapping antioxidant activity of copper and nickel Bis(Thiosemicarbazone) complexes underlies their potency as inhibitors of Ferroptotic cell death. J Am Chem Soc 2021; 143: 19043-57. https://doi.org/10.1021/jacs.1c08254.

[125] Soula M, Weber RA, Zilka O, Alwaseem H, La K, Yen F. et al. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat Chem Biol 2020; 16: 1351-60. https://doi.org/10.1038/s41589-020-0613-y.

[126] Duan W, Ou Z, Huang Y, Zhang Y, Zhang L, Zhao Y. et al. Silibinin inhibits cell Ferroptosis and Ferroptosis-related tissue injuries. Antioxidants (Basel, Switzerland) 2023; 12: 2119. https://doi.org/10.3390/antiox12122119.

[127] Wang W, Zhai T, Luo P, Miao X, Wang J, Chen Y. Beneficial effects of silibinin on serum lipids, bile acids, and gut microbiota in methionine-choline-deficient diet-induced mice. Front Nutr 2023; 10: 1257158. https://doi.org/10.3389/fnut.2023.1257158.

[128] Wortmann M, Schneider M, Pircher J, Hellfritsch J, Aichler M, Vegi N. et al. Combined deficiency in glutathione peroxidase 4 and vitamin E causes multiorgan thrombus formation and early death in mice. Circ Res 2013; 113: 408-17. https://doi.org/10.1161/CIRCRESAHA.113.279984.

[129] Carlson BA, Tobe R, Yefremova E, Tsuji PA, Hoffmann VJ, Schweizer U. et al. Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. Redox Biol 2016; 9: 22-31. https://doi.org/10.1016/j.redox.2016.05.003.

[130] Altamura S, Vegi NM, Hoppe PS, Schroeder T, Aichler M, Walch A. et al. Glutathione peroxidase 4 and vitamin E control reticulocyte maturation, stress erythropoiesis and iron homeostasis. Haematologica 2020; 105: 937-50. https://doi.org/10.3324/haematol.2018.212977.

[131] Hu Q, Zhang Y, Lou H, Ou Z, Liu J, Duan W. et al. GPX4 and vitamin E cooperatively protect hematopoietic stem and progenitor cells from lipid peroxidation and ferroptosis. Cell Death Dis 2021; 12: 706. https://doi.org/10.1038/s41419-021-04008-9.

[132] Kontoghiorghes GJ. Ethical issues and risk/benefit assessment of iron chelation therapy: advances with deferiprone/deferoxamine combinations and concerns about the safety, efficacy and costs of deferasirox. Hemoglobin 2008; 32: 1-15. https://doi.org/10.1080/03630260701726533.

[133] Zhu H, Cen J, Hong C, Wang H, Wen Y, He Q. et al. Targeting labile iron-mediated Ferroptosis provides a potential therapeutic strategy for rhabdomyolysis-induced acute kidney injury. ACS Chem Biol 2023; 18: 1294-304. https://doi.org/10.1021/acschembio.2c00914.

[134] Wang C, Xie L, Xing Y, Liu M, Yang J, Gao N. et al. Iron-overload-induced ferroptosis in mouse cerebral toxoplasmosis promotes brain injury and could be inhibited by Deferiprone. PLoS Negl Trop Dis 2023; 17: e0011607. https://doi.org/10.1371/journal.pntd.0011607.

[135] Hider RC, Hoffbrand AV. The role of Deferiprone in iron chelation. N Engl J Med 2018; 379: 2140-50. https://doi.org/10.1056/NEJMra1800219.

[136] Alim I, Caulfield JT, Chen Y, Swarup V, Geschwind DH, Ivanova E. et al. Selenium drives a transcriptional adaptive program to block Ferroptosis and treat stroke. Cell 2019; 177: 1262-1279.e25. https://doi.org/10.1016/j.cell.2019.03.032.

[137] Shchepinov MS. Polyunsaturated fatty acid Deuteration against neurodegeneration. Trends Pharmacol Sci 2020; 41: 236-48. https://doi.org/10.1016/j.tips.2020.01.010.

[138] Zesiewicz T, Heerinckx F, De Jager R, Omidvar O, Kilpatrick M, Shaw J. et al. Randomized, clinical trial of RT001: early signals of efficacy in Friedreich’s ataxia. Mov Disord 2018; 33: 1000-5. https://doi.org/10.1002/mds.27353.