NecroFerrins as dual therapeutic inhibitors targeting necroptosis and ferroptosis

Claire Delehouzé

1,*

Stéphane Bach

2,3,*

*Correspondence to: Claire Delehouzé, SeaBeLife Biotech, Place Georges Teissier, Roscoff 29680, France. E-mail: claire.delehouze@seabelife.com
Stéphane Bach, Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, Roscoff 29680, France; Sorbonne Université, CNRS, FR2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening facility), Station Biologique de Roscoff, Roscoff 29680, France. E-mail: bach@sb-roscoff.fr

Ferroptosis Oxid Stress. 2027;3:202623. 10.70401/fos.2026.0041

Received: May 19, 2026Accepted: August 05, 2026Published: August 05, 2026

This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

Over the past two decades, increasing attention has been devoted to regulated forms of cell death that occur independently of apoptosis. Among these, necroptosis and ferroptosis exhibit a necrotic-like morphology, yet are defined by distinct molecular and biochemical signatures. Both pathways have attracted considerable interest due to growing evidence implicating them in the pathogenesis of a wide range of acute and chronic disorders. Notably, the simultaneous engagement of multiple regulated necrosis pathways has been reported in many disease contexts, highlighting the limitations of single-target therapeutic approaches. In this light, the design of multi-target-directed ligands, that is, embracing a polypharmacological strategy, has emerged as a promising direction for development of future therapies. In this review, we propose the concept of NecroFerrins, a class of small molecules that simultaneously inhibit necroptosis and ferroptosis. Within this class, we identify RIPROStatins as a distinct subclass of RIPK1 inhibitors that additionally possess radical-trapping antioxidant activity. The objective of this review is also to stimulate translational research on complex diseases using polypharmacological drugs acting as necrosis inhibitors.

Keywords

Polypharmacology, ferroptosis, necroptosis, NecroFerrins, RIPROStatins

References

1. Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, et al. Classification of cell death: Recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 2009;16(1):3-11.

[DOI] [PubMed] [PMC]
2. Kerr JFR, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wideranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239-257.

[DOI]
3. Lockshin RA, Zakeri Z. Programmed cell death and apoptosis: Origins of the theory. Nat Rev Mol Cell Biol. 2001;2(7):545-550.

[DOI] [PubMed]
4. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25(3):486-541.

[DOI] [PubMed] [PMC]
5. Hadian K, Stockwell BR. The therapeutic potential of targeting regulated non-apoptotic cell death. Nat Rev Drug Discov. 2023;22(9):723-742.

[DOI]
6. Tang R, Xu J, Zhang B, Liu J, Liang C, Hua J, et al. Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J Hematol Oncol. 2020;13(1):110.

[DOI] [PubMed] [PMC]
7. Tang L, Liu S, Li S, Chen Y, Xie B, Zhou J. Induction mechanism of ferroptosis, necroptosis, and pyroptosis: A novel therapeutic target in nervous system diseases. Int J Mol Sci. 2023;24(12):10127.

[DOI] [PubMed] [PMC]
8. Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1(2):112-119.

[DOI] [PubMed]
9. Martinez-Osorio V, Abdelwahab Y, Ros U. The many faces of MLKL, the executor of necroptosis. Int J Mol Sci. 2023;24(12):10108.

[DOI]
10. 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(5):1060-1072.

[DOI] [PubMed] [PMC]
11. Dixon SJ, Olzmann JA. The cell biology of ferroptosis. Nat Rev Mol Cell Biol. 2024;25(6):424-442.

[DOI] [PubMed] [PMC]
12. Scarpellini C, Klejborowska G, Lanthier C, Hassannia B, Vanden Berghe T, Augustyns K. Beyond ferrostatin-1: A comprehensive review of ferroptosis inhibitors. Trends Pharmacol Sci. 2023;44(12):902-916.

[DOI] [PubMed]
13. Levkina A. The coming decade in ferroptosis research: Five riddles. Ferroptosis Oxid Stress. 2025;2:202516.

[DOI]
14. Lee E, Song CH, Bae SJ, Ha KT, Karki R. Regulated cell death pathways and their roles in homeostasis, infection, inflammation, and tumorigenesis. Exp Mol Med. 2023;55(8):1632-1643.

[DOI] [PubMed] [PMC]
15. Feinsod H, Stockwell BR. Fundamental mechanism of ferroptosis: Three unanswered questions. Ferroptosis Oxid Stress. 2026;2(2):202512.

[DOI] [PubMed] [PMC]
16. Dvoriantchikova G, Lypka KR, Adis EV, Ivanov D. Multiple types of programmed necrosis such as necroptosis, pyroptosis, oxytosis/ferroptosis, and parthanatos contribute simultaneously to retinal damage after ischemia-reperfusion. Sci Rep. 2022;12(1):17152.

[DOI] [PubMed] [PMC]
17. Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns versus magic bullets: Selectively non-selective drugs for mood disorders and schizophrenia. Nat Rev Drug Discov. 2004;3(4):353-359.

[DOI] [PubMed]
18. Abdelsayed M. AI-driven polypharmacology in small-molecule drug discovery. Int J Mol Sci. 2025;26(14):6996.

[DOI]
19. Morphy R, Rankovic Z. Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005;48(21):6523-6543.

[DOI]
20. Bolognesi ML. Polypharmacology in a single drug: Multitarget drugs. Curr Med Chem. 2013;20(13):1639-1645.

[DOI] [PubMed]
21. Ryszkiewicz P, Malinowska B, Schlicker E. Polypharmacology: Promises and new drugs in 2022. Pharmacol Rep. 2023;75(4):755-770.

[DOI]
22. Ryszkiewicz P, Malinowska B, Schlicker E. Polypharmacology: New drugs in 2023–2024. Pharmacol Rep. 2025;77(3):543-560.

[DOI]
23. Rochais C, Lecoutey C, Gaven F, Giannoni P, Hamidouche K, Hedou D, et al. Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT4R) agonist activities as potential agents against Alzheimer’s disease: The design of donecopride. J Med Chem. 2015;58(7):3172-3187.

[DOI] [PubMed]
24. Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem. 2008;51(3):347-372.

[DOI] [PubMed]
25. Delehouzé C, Mallais M, Comte A, Lucas R, Baratte B, Bélal S, et al. Sibiriline, a novel dual inhibitor of necroptosis and ferroptosis, prevents RIPK1 kinase activity and (phospho)lipid peroxidation as a potential therapeutic strategy. Cell Death Discov. 2025;11(1):552.

[DOI] [PubMed] [PMC]
26. Overington JP, Al-Lazikani B, Hopkins AL. How many drug targets are there? Nat Rev Drug Discov. 2006;5(12):993-996.

[DOI]
27. Li Y, Rasheed M, Liu J, Chen Z, Deng Y. Deciphering the molecular nexus: An in-depth review of mitochondrial pathways and their role in cell death crosstalk. Cells. 2024;13(10):863.

[DOI] [PubMed] [PMC]
28. Vanden Berghe T, Kaiser WJ, Bertrand MJ, Vandenabeele P. Molecular crosstalk between apoptosis, necroptosis, and survival signaling. Mol Cell Oncol. 2015;2(4):e975093.

[DOI]
29. Eskander G, Abdelhamid SG, Wahdan SA, Radwan SM. Insights on the crosstalk among different cell death mechanisms. Cell Death Discov. 2025;11:56.

[DOI]
30. Malireddi RKS, Kesavardhana S, Kanneganti TD. ZBP1 and TAK1: Master regulators of NLRP3 inflammasome/pyroptosis, apoptosis, and necroptosis (PAN-optosis). Front Cell Infect Microbiol. 2019;9:406.

[DOI]
31. Gao J, Xiong A, Liu J, Li X, Wang J, Zhang L, et al. PANoptosis: Bridging apoptosis, pyroptosis, and necroptosis in cancer progression and treatment. Cancer Gene Ther. 2024;31(7):970-983.

[DOI] [PubMed] [PMC]
32. Dixon SJ, Stockwell BR. The hallmarks of ferroptosis. Annu Rev Cancer Biol. 2019;3:35-54.

[DOI]
33. Jiang X, Stockwell BR, Conrad M. Ferroptosis: Mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021;22(4):266-282.

[DOI]
34. Tang D, Chen X, Kang R, Kroemer G. Ferroptosis: Molecular mechanisms and health implications. Cell Res. 2021;31(2):107-125.

[DOI] [PubMed] [PMC]
35. Jacobsen AV, Silke J. The importance of being chaperoned: HSP90 and necroptosis. Cell Chem Biol. 2016;23(2):205-207.

[DOI]
36. Wu Z, Geng Y, Lu X, Shi Y, Wu G, Zhang M, et al. Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc Natl Acad Sci U S A. 2019;116(8):2996-3005.

[DOI] [PubMed] [PMC]
37. Song C, Chen F, Fang Y, Ding X, Han Q, Duan Y, et al. The interaction between ferroptosis and necroptosis in acute and chronic kidney diseases. J Inflamm Res. 2026;19:1-15.

[DOI]
38. Pearl LH, Prodromou C, Workman P. The Hsp90 molecular chaperone: An open and shut case for treatment. Biochem J. 2008;410(3):439-453.

[DOI] [PubMed]
39. Chen WT, McKee NW, Kuhnell D, Dodson M. NRF2: Master regulator of cellular homeostasis and therapeutic vulnerability in cancer. Redox Biol. 2026;90:104050.

[DOI]
40. Müller T, Dewitz C, Schmitz J, Schröder AS, Bräsen JH, Stockwell BR, et al. Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure. Cell Mol Life Sci. 2017;74(19):3631-3645.

[DOI] [PubMed] [PMC]
41. Liang D, Minikes AM, Jiang X. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell. 2022;82(12):2215-2227.

[DOI]
42. Zhang L, Hu Z, Li Z, Lin Y. Crosstalk among mitophagy, pyroptosis, ferroptosis, and necroptosis in central nervous system injuries. Neural Regen Res. 2024;19(8):1660-1670.

[DOI] [PubMed] [PMC]
43. Tonnus W, Meyer C, Steinebach C, Belavgeni A, von Mässenhausen A, Gonzalez NZ, et al. Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nat Commun. 2021;12(1):4402.

[DOI] [PubMed] [PMC]
44. Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, et al. Ferroptosis: Past, present and future. Cell Death Dis. 2020;11(2):88.

[DOI] [PubMed] [PMC]
45. Mishima E, Nakamura T, Doll S, Proneth B, Fedorova M, Pratt DA, et al. Recommendations for robust and reproducible research on ferroptosis. Nat Rev Mol Cell Biol. 2025;26(8):615-630.

[DOI] [PubMed]
46. Helberg J, Pratt DA. Autoxidation vs. antioxidants–the fight for forever. Chem Soc Rev. 2021;50(13):7343-7358.

[DOI] [PubMed]
47. Zilka O, Shah R, Li B, Friedmann Angeli JP, Griesser M, Conrad M, et al. On the mechanism of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death. ACS Cent Sci. 2017;3(3):232-243.

[DOI]
48. Angeli JPF, 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(12):1180-1191.

[DOI] [PubMed] [PMC]
49. Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008;4(5):313-321.

[DOI] [PubMed] [PMC]
50. Le Cann F, Delehouzé C, Leverrier-Penna S, Filliol A, Comte A, Delalande O, et al. Sibiriline, a new small chemical inhibitor of receptor-interacting protein kinase 1, prevents immune-dependent hepatitis. FEBS J. 2017;284(18):3050-3068.

[DOI] [PubMed]
51. Pelletier R, Gicquel T, Simoes Eugenio M, Ferron PJ, Morel I, Delehouzé C, et al. A transversal approach combining in silico, in vitro and in vivo models to describe the metabolism of the receptor interacting protein 1 kinase inhibitor sibiriline. Pharmaceutics. 2022;14(12):2665.

[DOI] [PubMed] [PMC]
52. Vanden Berghe T, Grootjans S, Goossens V, Dondelinger Y, Krysko DV, Takahashi N, et al. Determination of apoptotic and necrotic cell death in vitro and in vivo. Methods. 2013;61(2):117-129.

[DOI] [PubMed]
53. Hu XM, Li ZX, Lin RH, Shan JQ, Yu QW, Wang RX, et al. Guidelines for regulated cell death assays: A systematic summary, a categorical comparison, a prospective. Front Cell Dev Biol. 2021;9:634690.

[DOI]
54. Yu X, Lin H, Li F, Wang J, Lu D. Development of biochemical and cellular probes to study RIPK1 target engagement. ACS Med Chem Lett. 2024;15(6):906-916.

[DOI]
55. Maki JL, Degterev A. Activity assays for receptor-interacting protein kinase 1: A key regulator of necroptosis. Methods Mol Biol. 2013;1004:31-42.

[DOI]
56. Najjar M, Suebsuwong C, Ray SS, Thapa RJ, Maki JL, Nogusa S, et al. Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1. Cell Rep. 2015;10(11):1850-1860.

[DOI] [PubMed] [PMC]
57. Maki JL, Brazell JT, Teng X, Cuny GD, Degterev A. Expression and purification of active receptor interacting protein 1 kinase using a baculovirus system. Protein Expr Purif. 2013;89(2):156-161.

[DOI]
58. Laurien L, Nagata M, Schünke H, Delanghe T, Wiederstein JL, Kumari S, et al. Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation. Nat Commun. 2020;11(1):1747.

[DOI] [PubMed] [PMC]
59. Tonnus W, Meyer C, Steinebach C, Belavgeni A, von Mässenhausen A, Gonzalez NZ, et al. Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nat Commun. 2021;12(1):4402.

[DOI] [PubMed] [PMC]
60. Patel S, Karlsson M, Klahn JT, Gambino F, Costa H, McGuire KA, et al. Quantitative target engagement of RIPK1 in human whole blood via the cellular thermal shift assay for potential pre-clinical and clinical applications. SLAS Discov. 2024;29(2):100135.

[DOI] [PubMed]
61. Shah R, Farmer LA, Zilka O, van Kessel ATM, Pratt DA. Beyond DPPH: Use of fluorescence-enabled inhibited autoxidation to predict oxidative cell death rescue. Cell Chem Biol. 2019;26(11):1594-1607.

[DOI] [PubMed]
62. Mallais M, Hanson CS, Giray M, Pratt DA. General approach to identify, assess, and characterize inhibitors of lipid peroxidation and associated cell death. ACS Chem Biol. 2023;18(3):561-571.

[DOI] [PubMed]
63. Al-Farhan A, Nayal OS, Pratt DA. Suppression of lipid peroxidation by necrostatins and their potential for dual targeting of ferroptosis and necroptosis. J Med Chem. 2026;69(14):17508-17523.

[DOI]
64. Charbonnel T, Richard E, Dupuis A, Palla M, Vourc’h P, Corcia P, et al. The preclinical discovery and development of edaravone for the treatment of amyotrophic lateral sclerosis: What lessons have we learnt? Expert Opin Drug Discov. 2026;21(2):147-160.

[DOI] [PubMed]
65. Xu B, Fang J, Wang J, Jin X, Liu S, Song K, et al. Inhibition of autophagy and RIP1/RIP3/MLKL-mediated necroptosis by edaravone attenuates blood spinal cord barrier disruption following spinal cord injury. Biomed Pharmacother. 2023;165:115165.

[DOI]
66. Song Z, Ye L, Wang Y, Wang W, Liu C, Lu J, et al. Targeting RIPK1-mediated necroptosis, oxidative stress, and ferroptosis: A novel multitarget therapy for ischemic stroke. Eur J Med Chem. 2025;296:117884.

[DOI]
67. Ji Y, Du S, Li J, Ma H, Wang X, Hao Y, et al. Discovery of Zharp1-163 as a dual inhibitor of ferroptosis and necroptosis for the treatment of inflammatory disorders and kidney injury. Cell Death Discov. 2025;11(1):413.

[DOI] [PubMed] [PMC]
68. Lin Y, Feng J, Zhao M, Zhang L, Li Y, Chen X, et al. Dovitinib ameliorates inflammation-related diseases by inhibiting necroptosis and ferroptosis. ACS Chem Biol. 2025;20(9):2191-2203.

[DOI]
69. Rui C, Shi SN, Ren W, Qin X, Zhuang C, Chen X, et al. The multitargeted kinase inhibitor KW-2449 ameliorates cisplatin-induced nephrotoxicity by targeting RIPK1-mediated necroptosis. Biochem Pharmacol. 2021;188:114542.

[DOI]
70. Zhao Y, Wang Q, Zhu J, Cai J, Feng X, Song Q, et al. Identification of KW-2449 as a dual inhibitor of ferroptosis and necroptosis reveals that autophagy is a targetable pathway for necroptosis inhibitors to prevent ferroptosis. Cell Death Dis. 2024;15(10):764.

[DOI] [PubMed] [PMC]
71. Delehouzé C, Leverrier-Penna S, Le Cann F, Comte A, Jacquard-Fevai M, Delalande O, et al. 6E11, a highly selective inhibitor of receptor-interacting protein kinase 1, protects cells against cold hypoxia-reoxygenation injury. Sci Rep. 2017;7(1):12931.

[DOI] [PubMed] [PMC]
72. Delehouzé C, Comte A, Leon-Icaza SA, Cougoule C, Hauteville M, Goekjian P, et al. Nigratine as dual inhibitor of necroptosis and ferroptosis regulated cell death. Sci Rep. 2022;12(1):5118.

[DOI] [PubMed] [PMC]
73. Lopes de Menezes DE, Peng J, Garrett EN, Louie SG, Lee SH, Wiesmann M, et al. CHIR-258: A potent inhibitor of FLT3 kinase in experimental tumor xenograft models of human acute myelogenous leukemia. Clin Cancer Res. 2005;11(14):5281-5291.

[DOI] [PubMed]
74. Guiffant D, Tribouillard D, Gug F, Galons H, Meijer L, Blondel M, et al. Identification of intracellular targets of small molecular weight chemical compounds using affinity chromatography. Biotechnol J. 2007;2(1):68-75.

[DOI] [PubMed]
75. Terstappen GC, Schlüpen C, Raggiaschi R, Gaviraghi G. Target deconvolution strategies in drug discovery. Nat Rev Drug Discov. 2007;6(11):891-903.

[DOI]
76. Lee J, Bogyo M. Target deconvolution techniques in modern phenotypic profiling. Curr Opin Chem Biol. 2013;17(1):118-126.

[DOI] [PubMed] [PMC]
77. Kitson RRA, Kitsonová D, Siegel D, Ross D, Moody CJ. Geldanamycin, a naturally occurring inhibitor of Hsp90 and a lead compound for medicinal chemistry. J Med Chem. 2024;67(20):17946-17963.

[DOI]
78. Reynolds TS, Mishra SJ, Blagg BSJ. Assessment of Hsp90β-selective inhibitor safety and on-target effects. Sci Rep. 2025;15:3692.

[DOI]
79. Deng XX, Li SS, Sun FY. Necrostatin-1 prevents necroptosis in brains after ischemic stroke via inhibition of RIPK1-mediated RIPK3/MLKL signaling. Aging Dis. 2019;10(4):807-817.

[DOI] [PubMed] [PMC]
80. Chen F, Su X, Lin Z, Lin Y, Yu L, Cai J, et al. Necrostatin-1 attenuates early brain injury after subarachnoid hemorrhage in rats by inhibiting necroptosis. Neuropsychiatr Dis Treat. 2017;13:1771-1782.

[DOI]
81. Chen J, Jin H, Xu H, Peng Y, Jie L, Xu D, et al. The neuroprotective effects of necrostatin-1 on subarachnoid hemorrhage in rats are possibly mediated by preventing blood-brain barrier disruption and RIP3-mediated necroptosis. Cell Transplant. 2019;28(11):1358-1372.

[DOI] [PubMed] [PMC]
82. Qin Q, Yu N, Gu Y, Ke W, Zhang Q, Liu X, et al. Inhibiting multiple forms of cell death optimizes ganglion cells survival after retinal ischemia reperfusion injury. Cell Death Dis. 2022;13(5):507.

[DOI] [PubMed] [PMC]
83. Liu M, Li H, Yang R, Ji D, Xia X. GSK872 and necrostatin-1 protect retinal ganglion cells against necroptosis through inhibition of RIP1/RIP3/MLKL pathway in glutamate-induced retinal excitotoxic model of glaucoma. J Neuroinflammation. 2022;19(1):262.

[DOI] [PubMed] [PMC]
84. Liu YR, Xu HM. Protective effect of necrostatin-1 on myocardial tissue in rats with acute myocardial infarction. Genet Mol Res. 2016;15(2):gmr7298.

[DOI] [PubMed]
85. Ning Y, Shi Y, Chen J, Song N, Cai J, Fang Y, et al. Necrostatin-1 attenuates cisplatin-induced nephrotoxicity through suppression of apoptosis and oxidative stress and retains Klotho expression. Front Pharmacol. 2018;9:384.

[DOI]
86. Shen B, Mei M, Pu Y, Zhang H, Liu H, Tang M, et al. Necrostatin-1 attenuates renal ischemia and reperfusion injury via meditation of HIF-1α/mir-26a/TRPC6/PARP1 signaling. Mol Ther Nucleic Acids. 2019;17:701-713.

[DOI]
87. Takemoto K, Hatano E, Iwaisako K, Takeiri M, Noma N, Ohmae S, et al. Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure. FEBS Open Bio. 2014;4(1):777-787.

[DOI]
88. Ito K, Ozasa H, Horikawa S. Edaravone protects against lung injury induced by intestinal ischemia/reperfusion in rat. Free Radic Biol Med. 2005;38(3):369-374.

[DOI] [PubMed]
89. Zhang Z, Luo Z, Bi A, Yang W, An W, Dong X, et al. Compound edaravone alleviates lipopolysaccharide (LPS)-induced acute lung injury in mice. Eur J Pharmacol. 2017;811:1-11.

[DOI]
90. Liu H, Zhang M, Dong X, Liu Y, Hao Y, Wang Y. Necrostatin-1 protects against ischemia/reperfusion injury by inhibiting receptor-interacting protein 1 in a rat flap model. J Plast Reconstr Aesthet Surg. 2019;72(2):194-202.

[DOI] [PubMed]
91. Lin B, Jin Z, Chen X, Zhao L, Weng C, Chen B, et al. Necrostatin-1 protects mice from acute lung injury by suppressing necroptosis and reactive oxygen species. Mol Med Rep. 2020;21(5):2171-2181.

[DOI]
92. Linkermann A, Skouta R, Himmerkus N, Mulay SR, Dewitz C, De Zen F, et al. Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci U S A. 2014;111(47):16836-16841.

[DOI] [PubMed] [PMC]
93. Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife. 2014;3:e02523.

[DOI]
94. Ding R, Tang L, Zeng D, Li J, Jia Y, Yan X, et al. Discovery of novel JQ1 derivatives as dual ferroptosis and apoptosis inducers for the treatment of triple-negative breast cancer. Eur J Med Chem. 2025;286:117275.

[DOI]
95. Linkermann A. Key questions in ferroptosis. Ferroptosis Oxid Stress. 2025;1(1):202503.

[DOI]
96. He S, Huang S, Shen Z. Biomarkers for the detection of necroptosis. Cell Mol Life Sci. 2016;73(11-12):2177-2181.

[DOI] [PubMed] [PMC]
97. Chen X, Comish PB, Tang D, Kang R. Characteristics and biomarkers of ferroptosis. Front Cell Dev Biol. 2021;9:637162.

[DOI]
98. Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: The release of damage-associated molecular patterns and its physiological relevance. Immunity. 2013;38(2):209-223.

[DOI] [PubMed]
99. Cichońska A, Ravikumar B, Rahman R. AI for targeted polypharmacology: The next frontier in drug discovery. Curr Opin Struct Biol. 2024;84:102771.

[DOI]
100. Homma T, Kobayashi S, Sato H, Fujii J. Edaravone, a free radical scavenger, protects against ferroptotic cell death in vitro. Exp Cell Res. 2019;384(1):111592.

[DOI] [PubMed]
101. Ushijima H, Monzaki R. An in vitro evaluation of the antioxidant activities of necroptosis and apoptosis inhibitors: The potential of necrostatin-1 and necrostatin-1i to have radical scavenging activities. Pharmacol Rep. 2023;75(2):490-497.

[DOI] [PubMed]
102. Winardi W, Lo YP, Tsai HP, Huang YH, Tseng TT, Chung CL. CDDO, an anti-inflammatory and antioxidant compound, attenuates vasospasm and neuronal cell apoptosis in rats subjected to experimental subarachnoid hemorrhage. Curr Issues Mol Biol. 2024;46(5):4688-4700.

[DOI] [PubMed] [PMC]

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Delehouzé C, Bach S. NecroFerrins as dual therapeutic inhibitors targeting necroptosis and ferroptosis. Ferroptosis Oxid Stress. 2027;3:202623. https://doi.org/10.70401/fos.2026.0041