This is an unedited manuscript accepted for publication and provided as an Article in Press for early access at the author’s request. The article will undergo copyediting, typesetting, and galley proof review before final publication. Please be aware that errors may be identified during production that could affect the content. All legal disclaimers of the journal apply.
Sarbjot Singh*,
Gaurav Singh,
Anita Devi,
Aaditya Thakur,
Harshit Sharma,
Sheetal Thakur,
Anish Verma,
Itisha Ranjani,
- Associate Professor, Department of Pharmacology, Himachal Pharmacy College, Majhauli (Nalagarh), Himachal Pradesh, India
- Student, of Pharmacy, Himachal Pharmacy College, Majhauli (Nalagarh), Himachal Pradesh, India
- Assistant Professor, ,Department of Pharmaceutical Chemistry, Himachal Pharmacy College, Majhauli (Nalagarh), Himachal Pradesh, India
- Student, Bachelor of Pharmacy, Himachal Pharmacy College, Majhauli (Nalagarh), Himachal Pradesh, India
- Student, Year),Bachelor of Pharmacy, Himachal Pharmacy College, Majhauli (Nalagarh), Himachal Pradesh, India
- Student, Year),Bachelor of Pharmacy, Himachal Pharmacy College, Majhauli (Nalagarh), Himachal Pradesh, India
- Research Scholar, Scholar,Department of Pharmacology, Amar Shaheed Baba Ajeet Singh Jhujhar Singh Memorial College,Bela(Ropar), Punjab, India
- Student, Bachelor of Dental Surgery, Bachelor of Dental Surgery., Kalka Dental College & Hospital (Meerut), Uttar Pradesh, India
Abstract
For a long time, oxidative stress was cast as a plain villain, something to be pushed down with antioxidants wherever it appeared. That view has changed. Reactive oxygen species (ROS) do real work in the cell. At low concentrations, molecules such as hydrogen peroxide act as signals. As stress increases, cells activate protective mechanisms to keep themselves safe. However, if the stress becomes too strong or lasts too long, these defenses fail, and the cell undergoes regulated cell death. . We describe this sequence as one continuous scale, the “redox rheostat.” Where a given cell sits on it depends on how much ROS is produced, for how long, in which compartment, and on the state the cell was in beforehand. This review follows ROS through signaling, adaptation, and the main forms of regulated cell death, with particular attention to Nrf2-Keap1, ferroptosis, apoptosis, necroptosis, and pyroptosis. We examine drugs that act on redox pathways, organ toxicities driven by redox imbalance (acetaminophen in the liver, doxorubicin in the heart, and cisplatin in the kidney and inner ear), and the reasons why blanket antioxidant therapy has so often disappointed. We close with targeted delivery, biomarkers, and the prospects for more precise redox pharmacology. The central message is simple: oxidative stress is not a single condition with a single remedy. What it does to a cell depends on dose, timing, location and cellular context.
Keywords: reactive oxygen species, redox signaling, oxidative stress, redox rheostat, stress
References
1. Sies H. Oxidative stress: a concept in redox biology and medicine. Redox biology. 2015 Apr 1;4:180-3.
2. Sies H, Berndt C, Jones DP. Oxidative stress. Annual review of biochemistry. 2017 Jun 20;86:715-48.
3. Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nature reviews Molecular cell biology. 2020 Jul 15;21(7):363-83.
4. Sies H. Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress. Redox biology. 2017 Apr 1;11:613-9.
5. Brandes RP, Weissmann N, Schröder K. Nox family NADPH oxidases: molecular mechanisms of activation. Free Radical Biology and Medicine. 2014 Nov 1;76:208- 26.
6. Brand MD. Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radical Biology and Medicine. 2016 Nov 1;100:14-31.
7. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. Jama. 2007 Feb 28;297(8):842-57.
8. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death & Differentiation. 2018 Mar;25(3):486-541.
9. Calabrese EJ, Baldwin LA. Hormesis: the dose-response revolution. Annual review of pharmacology and toxicology. 2003 Apr;43(1):175-97.
10. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiological reviews. 2014 Jul;94(3):909-50.
11. Bienert GP, Schjoerring JK, Jahn TP. Membrane transport of hydrogen peroxide. Biochimica et Biophysica Acta (BBA)-Biomembranes. 2006 Aug 1;1758(8):994- 1003.
12. Winterbourn CC, Hampton MB. Thiol chemistry and specificity in redox signaling. Free Radical Biology and Medicine. 2008 Sep 1;45(5):549-61.
13. Sies H, Belousov VV, Chandel NS, Davies MJ, Jones DP, Mann GE, Murphy MP, Yamamoto M, Winterbourn C. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nature reviews Molecular cell biology. 2022 Jul;23(7):499-515.
14. Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Current biology. 2014 May 19;24(10):R453-62.
15. Hanschmann EM, Godoy JR, Berndt C, Hudemann C, Lillig CH. Thioredoxins, glutaredoxins, and peroxiredoxins—molecular mechanisms and health significance: from cofactors to antioxidants to redox signaling. Antioxidants & redox signaling. 2013 Nov;19(13):1539-605.
16. Biteau B, Labarre J, Toledano MB. ATP-dependent reduction of cysteine–sulphinic acid by S. cerevisiae sulphiredoxin. Nature. 2003 Oct 30;425(6961):980-4.
17. Lee SR, Kwon KS, Kim SR, Rhee SG. Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. Journal of Biological Chemistry. 1998 Jun 19;273(25):15366-72.
18. Wood ZA, Poole LB, Karplus PA. Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science. 2003 Apr 25;300(5619):650-3.
19. Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 system: a thiol- based sensor-effector apparatus for maintaining redox homeostasis. Physiological reviews. 2018 Jul 1;98(3):1169-203.
20. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol.. 2007 Feb 10;47(1):89-116.
21. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. science. 2011 Nov 25;334(6059):1081-6.
22. Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nature reviews Molecular cell biology. 2020 Aug;21(8):421-38.
23. Pickles S, Vigié P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Current Biology. 2018 Feb 19;28(4):R170-85.
24. Ristow M, Zarse K. How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis). Experimental gerontology. 2010 Jun 1;45(6):410-8.
25. Ristow M, Zarse K, Oberbach A, Klöting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR, Blüher M. Antioxidants prevent health-promoting effects of physical exercise in humans. Proceedings of the National Academy of Sciences. 2009 May 26;106(21):8665-70.
26. Bernardi P, Di Lisa F. The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection. Journal of molecular and cellular cardiology. 2015 Jan 1;78:100-6.
27. Hotchkiss RS, Strasser A, McDunn JE. Swanson, PE 2009. Cell death. New Englandjournal of Medicine. 86;361:1570-83
. 28. Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nature reviews Molecular cell biology. 2010 Sep;11(9):621-32.
29. Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation. Nature. 2015 Jan 15;517(7534):311-20.
30. Shi J, Gao W, Shao F. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends in biochemical sciences. 2017 Apr 1;42(4):245-54.
31. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011 Jan 13;469(7329):221-5.
32. Fatokun AA, Dawson VL, Dawson TM. Parthanatos: mitochondrial‐linked mechanisms and therapeutic opportunities. British journal of pharmacology. 2014 Apr;171(8):2000-16. 3
33. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B. Ferroptosis: an iron- dependent form of nonapoptotic cell death. cell. 2012 May 25;149(5):1060-72.
34. Stockwell BR, Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. cell. 2017 Oct 5;171(2):273-85.
35. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler M, Beckers J, Aichler M, Walch A, Prokisch H. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nature chemical biology. 2017 Jan;13(1):91-8.
36. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014 Jan 16;156(1):317-31.
37. Ursini F, Maiorino M. Lipid peroxidation and ferroptosis: the role of GSH and GPx4. Free Radical Biology and Medicine. 2020 May 20;152:175-85.
38. Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, Goya Grocin A, Xavier da Silva TN, Panzilius E, Scheel CH, Mourão A. FSP1 is a glutathione- independent ferroptosis suppressor. Nature. 2019 Nov 28;575(7784):693-8.
39. Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, Roberts MA, Tong B, Maimone TJ, Zoncu R, Bassik MC. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019 Nov 28;575(7784):688-92.
40. Kraft VA, Bezjian CT, Pfeiffer S, Ringelstetter L, Müller C, Zandkarimi F, Merl- Pham J, Bao X, Anastasov N, Kössl J, Brandner S. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS central science. 2020 Jan 22;6(1):41-53.
41. Dixon SJ, Stockwell BR. The hallmarks of ferroptosis. Annual review of cancer biology. 2019 Mar 4;3:35-54.
42. Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nature reviews Molecular cell biology. 2021 Apr;22(4):266-82.
43. Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, Rossen J, Joesch-Cohen L, Humeidi R, Spangler RD, Eaton JK. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022 Mar 18;375(6586):1254-61.
44. Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP, Rumsey WL, Attucks OC, Franklin S, Levonen AL, Kensler TW, Dinkova-Kostova AT. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nature reviews Drug discovery. 2019 Apr;18(4):295-317.
45. Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011 Mar 1;134(3):678-92.
46. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. New England Journal of Medicine. 2012 Sep 20;367(12):1098-107.
47. De Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, Goldsberry A, Houser M, Krauth M, Lambers Heerspink HJ, McMurray JJ. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. New England Journal of Medicine. 2013 Dec 26;369(26):2492-503.
48. de la Vega MR, Chapman E, Zhang DD. NRF2 and the Hallmarks of Cancer. Cancer cell. 2018 Jul 9;34(1):21-43.
49. Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, Kaffenberger SD, Eaton JK, Shimada K, Aguirre AJ, Viswanathan SR. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017 Jul 27;547(7664):453-7.
50. Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, Basavarajappa D. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature cell biology. 2014 Dec;16(12):1180-91.
51. Zilka O, Shah R, Li B, Friedmann Angeli JP, Griesser M, Conrad M, Pratt DA. On the mechanism of cytoprotection by ferrostatin1 and liproxstatin1 and the role of lipid peroxidation in ferroptotic cell death. ACS central science. 2017 Mar 22;3(3):232-43.
52. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nature medicine. 2013 Feb;19(2):202-8.
53. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. New England Journal of Medicine. 2016 Jan 28;374(4):311-22.
54. Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature chemical biology. 2005 Jul;1(2):112-9.
55. Coll RC, Schroder K, Pelegrín P. NLRP3 and pyroptosis blockers for treating inflammatory diseases. Trends in pharmacological sciences. 2022 Aug 1;43(8):653- 68.
56. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nature reviews Drug discovery. 2013 Dec;12(12):931-47.
57. Jaeschke H, McGill MR, Ramachandran A. Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug metabolism reviews. 2012 Feb 1;44(1):88-106.
58. Prescott LF, Illingworth RN, Critchley JA, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. British medical journal. 1979 Nov 3;2(6198):1097-100.
59. Fang X, Wang H, Han D, Xie E, Yang X, Wei J, Gu S, Gao F, Zhu N, Yin X, Cheng Q. Ferroptosis as a target for protection against cardiomyopathy. Proceedings of the National Academy of Sciences. 2019 Feb 12;116(7):2672-80.
60. Swain SM, Whaley FS, Gerber MC, Weisberg S, York M, Spicer D, Jones SE, Wadler S, Desai A, Vogel C, Speyer J. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. Journal of clinical oncology. 1997 Apr;15(4):1318-32.
61. Manohar S, Leung N. Cisplatin nephrotoxicity: a review of the literature. Journal of nephrology. 2018 Feb 1;31(1):15-25.
62. Rybak LP, Mukherjea D, Ramkumar V. Mechanisms of cisplatin-induced ototoxicity and prevention. In Seminars in hearing 2019 May (Vol. 40, No. 02, pp. 197-204). Thieme Medical Publishers.
63. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. New England Journal of Medicine. 2008 Jul 31;359(5):473-81.
64. Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, Bonnefoy-Cudraz E, Guérin P, Elbaz M, Delarche N, Coste P. Cyclosporine before PCI in patients with acute myocardial infarction. New England Journal of Medicine. 2015 Sep 10;373(11):1021-31.
65. Poljsak B, Šuput D, Milisav I. Achieving the balance between ROS and antioxidants: when to use the synthetic antioxidants. Oxidative medicine and cellular longevity. 2013;2013(1):956792.
66. Smith RA, Murphy MP. Animal and human studies with the mitochondria‐targeted antioxidant MitoQ. Annals of the new York Academy of Sciences. 2010 Jul;1201(1):96-103.
67. Szeto HH. First‐in‐class cardiolipin‐protective compound as a therapeutic agent to restore mitochondrial bioenergetics. British journal of pharmacology. 2014 Apr;171(8):2029-50.
68. Tao W, He Z. ROS-responsive drug delivery systems for biomedical applications. asian journal of pharmaceutical sciences. 2018 Mar 1;13(2):101-12.
69. Rittié L, Fisher GJ. UV-light-induced signal cascades and skin aging. Ageing research reviews. 2002 Sep 1;1(4):705-20.
70. Pinnell SR, Yang H, Omar M, Riviere NM, Debuys HV, Walker LC, Wang Y, Levine M. Topical L‐ascorbic acid: percutaneous absorption studies. Dermatologic surgery. 2001 Feb;27(2):137-42.
71. Kalyanaraman B, Darley-Usmar V, Davies KJ, Dennery PA, Forman HJ, Grisham MB, Mann GE, Moore K, Roberts II LJ, Ischiropoulos H. Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free radical biology and medicine. 2012 Jan 1;52(1):1-6.
72. Forman HJ, Augusto O, Brigelius-Flohe R, Dennery PA, Kalyanaraman B, Ischiropoulos H, Mann GE, Radi R, Roberts II LJ, Vina J, Davies KJ. Even free radicals should follow some rules: a guide to free radical research terminology and methodology. Free Radical Biology and Medicine. 2015 Jan 1;78:233-5.
73. Gutscher M, Pauleau AL, Marty L, Brach T, Wabnitz GH, Samstag Y, Meyer AJ, Dick TP. Real-time imaging of the intracellular glutathione redox potential. Nature methods. 2008 Jun;5(6):553-9.
74. Belousov VV, Fradkov AF, Lukyanov KA, Staroverov DB, Shakhbazov KS, Terskikh AV, Lukyanov S. Genetically encoded fluorescent indicator for intracellular hydrogen peroxide. Nature methods. 2006 Apr;3(4):281-6.
International Journal of Cell Biology and Cellular Functions
| Volume | 04 | |
| 02 | ||
| Received | 08/10/2026 | |
| Accepted | 14/10/2026 | |
| Published | 24/10/2026 | |
| Publication Time | 16 Days |