Research progress on ubiquitination modification in sepsis_West China Medical Journal

Authors：

LIU Jia , LI Runze , YIN Mingchen ,  LIU Chang ,  SHEN Yanna

Division of Medical Technology, Tianjin Medical University, Tianjin 300203, P. R. China;

Corresponding author：

LIU Chang, Email: liuchang419@tmu.edu.cn; SHEN Yanna, Email: shenyanna@tmu.edu.cn

Keywords：

Ubiquitination; sepsis; treatment strategy

DOI：

10.7507/1002-0179.202507289

Video：

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Abstract Full text Figures/Tables Video References Cited by

Sepsis is a multiple organ dysfunction syndrome caused by a dysregulated host response to infection. The mortality rate remains high under current treatment methods, and there is an urgent need to explore new therapeutic targets. Ubiquitination modification, as a key posttranslational regulation mechanism of proteins, plays a central role in the occurrence and development of sepsis and multiple organ damage by regulating key pathological processes such as inflammatory response, cell death and barrier function. This article aims to systematically elucidate the molecular mechanism of ubiquitination modification system in sepsis related organ damage, summarize the latest research progress on treatment strategies targeting the ubiquitination pathway, and explore the challenges and future transformation directions faced in this field. Through comprehensive analysis of existing research, this review aims to provide new ideas and theoretical basis for precise treatment of sepsis.

Citation： LIU Jia, LI Runze, YIN Mingchen, LIU Chang, SHEN Yanna. Research progress on ubiquitination modification in sepsis. West China Medical Journal, 2025, 40(8): 1313-1316. doi: 10.7507/1002-0179.202507289 Copy

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2.	Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet, 2020, 395(10219): 200-211.
3.	Perner A, Cecconi M, Cronhjort M, et al. Expert statement for the management of hypovolemia in sepsis. Intensive Care Med, 2018, 44(6): 791-798.
4.	Liu YC, Yao Y, Yu MM, et al. Frequency and mortality of sepsis and septic shock in China: a systematic review and meta-analysis. BMC Infect Dis, 2022, 22(1): 564.
5.	Cecconi M, Evans L, Levy M, et al. Sepsis and septic shock. Lancet, 2018, 392(10141): 75-87.
6.	Martínez-Férriz A, Ferrando A, Fathinajafabadi A, et al. Ubiquitin-mediated mechanisms of translational control. Semin Cell Dev Biol, 2022, 132: 146-154.
7.	Yau R, Rape M. The increasing complexity of the ubiquitin code. Nat Cell Biol, 2016, 18(6): 579-586.
8.	Nakamura N. Ubiquitin system. Int J Mol Sci, 2018, 19(4): 1080.
9.	Sheng X, Xia Z, Yang H, et al. The ubiquitin codes in cellular stress responses. Protein Cell, 2024, 15(3): 157-190.
10.	Chen MY, Liu Y, Fang M. The role of protein ubiquitination in the onset and progression of sepsis. Cells, 2025, 14(13): 1012.
11.	Jiang T, Peng D, Shi W, et al. IL-6/STAT3 signaling promotes cardiac dysfunction by upregulating FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes formation in sepsis mice. Front Cardiovasc Med, 2022, 8: 790612.
12.	Wang R, Xu Y, Fang Y, et al. Pathogenetic mechanisms of septic cardiomyopathy. J Cell Physiol, 2022, 237(1): 49-58.
13.	Tang X, Weng R, Guo G, et al. USP10 regulates macrophage inflammation responses via stabilizing NEMO in LPS-induced sepsis. Inflamm Res, 2023, 72(8): 1621-1632.
14.	Ma M, Cao R, Tian Y, et al. Ubiquitination and metabolic disease. Adv Exp Med Biol, 2024, 1466: 47-79.
15.	Liu F, Chen J, Li K, et al. Ubiquitination and deubiquitination in cancer: from mechanisms to novel therapeutic approaches. Mol Cancer, 2024, 23(1): 148.
16.	Cheng L, Feng B, Xie C, et al. Overexpression of miR-20a targeting DUSP3 inhibits OCLN ubiquitination levels and alleviates sepsis induced intestinal barrier dysfunction. In Vitro Cell Dev Biol Anim, 2025, 61(4): 459-471.
17.	Qian Y, Wang Z, Lin H, et al. TRIM47 is a novel endothelial activation factor that aggravates lipopolysaccharide-induced acute lung injury in mice via K63-linked ubiquitination of TRAF2. Signal Transduct Target Ther, 2022, 7(1): 148.
18.	Zhu W, Zhang Q, Jin L, et al. OTUD1 deficiency alleviates LPS-induced acute lung injury in mice by reducing inflammatory response. Inflammation, 2025, 48(2): 649-661.
19.	Liu H, Jing G, Wu S, et al. Acod1 promotes PAD4 ubiquitination via UBR5 alkylation to modulate NETosis and exert protective effects in sepsis. Adv Sci (Weinh), 2025, 30: e11652.
20.	Wu F, Zhang YT, Teng F, et al. S100a8/a9 contributes to sepsis-induced cardiomyopathy by activating ERK1/2-Drp1-mediated mitochondrial fission and respiratory dysfunction. Int Immunopharmacol, 2023, 115: 109716.
21.	Liao J, Su X, Wang M, et al. The E3 ubiquitin ligase CHIP protects against sepsis-induced myocardial dysfunction by inhibiting NF-κB-mediated inflammation via promoting ubiquitination and degradation of karyopherin-α 2. Transl Res, 2023, 255: 50-65.
22.	Wang Z, Sun S, Huang L, et al. METTL3/YTHDF1-mediated m6A modification stabilizes USP12 to deubiquitinate FOXO3 and promote apoptosis in sepsis-induced myocardial dysfunction. Mol Immunol, 2025, 177: 17-31.
23.	Sun HJ, Zheng GL, Wang ZC, et al. Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming. Phytomedicine, 2024, 123: 155175.
24.	Ma Y, Mouton AJ, Lindsey ML. Cardiac macrophage biology in the steady-state heart, the aging heart, and following myocardial infarction. Transl Res, 2018, 191: 15-28.
25.	Yu Y, Fu Q, Li J, et al. E3 ubiquitin ligase COP1-mediated CEBPB ubiquitination regulates the inflammatory response of macrophages in sepsis-induced myocardial injury. Mamm Genome, 2024, 35(1): 56-67.
26.	Gao W, Wang L, Li Z. Ubiquitin-specific protease 8 regulates cognitive dysfunction of mice with sepsis-associated encephalopathy through SIRT1 deubiquitination. Curr Neurovasc Res, 2023: 12.
27.	Shen W, Zhang X, Tang M, et al. Targeting of ubiquitination and degradation of KLF15 by E3 ubiquitin ligase KBTBD7 regulates LPS-induced septic brain injury in microglia. Exp Cell Res, 2024, 443(1): 114317.
28.	Matsuo S, Sharma A, Wang P, et al. PYR-41, a ubiquitin-activating enzyme E1 inhibitor, attenuates lung injury in sepsis. Shock, 2018, 49(4): 442-450.
29.	Dao L, Liu H, Xiu R, et al. Gramine improves sepsis-induced myocardial dysfunction by binding to NF-κB p105 and inhibiting its ubiquitination. Phytomedicine, 2024, 125: 155325.
30.	Liu Y, Hu N, Ai B, et al. MiR-31-5p alleviates septic cardiomyopathy by targeting BAP1 to inhibit SLC7A11 deubiquitination and ferroptosis. BMC Cardiovasc Disord, 2024, 24(1): 286.
31.	Luo Y, Li Y, He L, et al. Xinyang tablet ameliorates sepsis-induced myocardial dysfunction by regulating Beclin-1 to mediate macrophage autophagy and M2 polarization through LncSICRNT1 targeting E3 ubiquitin ligase TRAF6. Chin Med, 2023, 18(1): 143.

1. Hollenberg SM, Singer M. Pathophysiology of sepsis-induced cardiomyopathy. Nat Rev Cardiol, 2021, 18(6): 424-434.
2. Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet, 2020, 395(10219): 200-211.
3. Perner A, Cecconi M, Cronhjort M, et al. Expert statement for the management of hypovolemia in sepsis. Intensive Care Med, 2018, 44(6): 791-798.
4. Liu YC, Yao Y, Yu MM, et al. Frequency and mortality of sepsis and septic shock in China: a systematic review and meta-analysis. BMC Infect Dis, 2022, 22(1): 564.
5. Cecconi M, Evans L, Levy M, et al. Sepsis and septic shock. Lancet, 2018, 392(10141): 75-87.
6. Martínez-Férriz A, Ferrando A, Fathinajafabadi A, et al. Ubiquitin-mediated mechanisms of translational control. Semin Cell Dev Biol, 2022, 132: 146-154.
7. Yau R, Rape M. The increasing complexity of the ubiquitin code. Nat Cell Biol, 2016, 18(6): 579-586.
8. Nakamura N. Ubiquitin system. Int J Mol Sci, 2018, 19(4): 1080.
9. Sheng X, Xia Z, Yang H, et al. The ubiquitin codes in cellular stress responses. Protein Cell, 2024, 15(3): 157-190.
10. Chen MY, Liu Y, Fang M. The role of protein ubiquitination in the onset and progression of sepsis. Cells, 2025, 14(13): 1012.
11. Jiang T, Peng D, Shi W, et al. IL-6/STAT3 signaling promotes cardiac dysfunction by upregulating FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes formation in sepsis mice. Front Cardiovasc Med, 2022, 8: 790612.
12. Wang R, Xu Y, Fang Y, et al. Pathogenetic mechanisms of septic cardiomyopathy. J Cell Physiol, 2022, 237(1): 49-58.
13. Tang X, Weng R, Guo G, et al. USP10 regulates macrophage inflammation responses via stabilizing NEMO in LPS-induced sepsis. Inflamm Res, 2023, 72(8): 1621-1632.
14. Ma M, Cao R, Tian Y, et al. Ubiquitination and metabolic disease. Adv Exp Med Biol, 2024, 1466: 47-79.
15. Liu F, Chen J, Li K, et al. Ubiquitination and deubiquitination in cancer: from mechanisms to novel therapeutic approaches. Mol Cancer, 2024, 23(1): 148.
16. Cheng L, Feng B, Xie C, et al. Overexpression of miR-20a targeting DUSP3 inhibits OCLN ubiquitination levels and alleviates sepsis induced intestinal barrier dysfunction. In Vitro Cell Dev Biol Anim, 2025, 61(4): 459-471.
17. Qian Y, Wang Z, Lin H, et al. TRIM47 is a novel endothelial activation factor that aggravates lipopolysaccharide-induced acute lung injury in mice via K63-linked ubiquitination of TRAF2. Signal Transduct Target Ther, 2022, 7(1): 148.
18. Zhu W, Zhang Q, Jin L, et al. OTUD1 deficiency alleviates LPS-induced acute lung injury in mice by reducing inflammatory response. Inflammation, 2025, 48(2): 649-661.
19. Liu H, Jing G, Wu S, et al. Acod1 promotes PAD4 ubiquitination via UBR5 alkylation to modulate NETosis and exert protective effects in sepsis. Adv Sci (Weinh), 2025, 30: e11652.
20. Wu F, Zhang YT, Teng F, et al. S100a8/a9 contributes to sepsis-induced cardiomyopathy by activating ERK1/2-Drp1-mediated mitochondrial fission and respiratory dysfunction. Int Immunopharmacol, 2023, 115: 109716.
21. Liao J, Su X, Wang M, et al. The E3 ubiquitin ligase CHIP protects against sepsis-induced myocardial dysfunction by inhibiting NF-κB-mediated inflammation via promoting ubiquitination and degradation of karyopherin-α 2. Transl Res, 2023, 255: 50-65.
22. Wang Z, Sun S, Huang L, et al. METTL3/YTHDF1-mediated m6A modification stabilizes USP12 to deubiquitinate FOXO3 and promote apoptosis in sepsis-induced myocardial dysfunction. Mol Immunol, 2025, 177: 17-31.
23. Sun HJ, Zheng GL, Wang ZC, et al. Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming. Phytomedicine, 2024, 123: 155175.
24. Ma Y, Mouton AJ, Lindsey ML. Cardiac macrophage biology in the steady-state heart, the aging heart, and following myocardial infarction. Transl Res, 2018, 191: 15-28.
25. Yu Y, Fu Q, Li J, et al. E3 ubiquitin ligase COP1-mediated CEBPB ubiquitination regulates the inflammatory response of macrophages in sepsis-induced myocardial injury. Mamm Genome, 2024, 35(1): 56-67.
26. Gao W, Wang L, Li Z. Ubiquitin-specific protease 8 regulates cognitive dysfunction of mice with sepsis-associated encephalopathy through SIRT1 deubiquitination. Curr Neurovasc Res, 2023: 12.
27. Shen W, Zhang X, Tang M, et al. Targeting of ubiquitination and degradation of KLF15 by E3 ubiquitin ligase KBTBD7 regulates LPS-induced septic brain injury in microglia. Exp Cell Res, 2024, 443(1): 114317.
28. Matsuo S, Sharma A, Wang P, et al. PYR-41, a ubiquitin-activating enzyme E1 inhibitor, attenuates lung injury in sepsis. Shock, 2018, 49(4): 442-450.
29. Dao L, Liu H, Xiu R, et al. Gramine improves sepsis-induced myocardial dysfunction by binding to NF-κB p105 and inhibiting its ubiquitination. Phytomedicine, 2024, 125: 155325.
30. Liu Y, Hu N, Ai B, et al. MiR-31-5p alleviates septic cardiomyopathy by targeting BAP1 to inhibit SLC7A11 deubiquitination and ferroptosis. BMC Cardiovasc Disord, 2024, 24(1): 286.
31. Luo Y, Li Y, He L, et al. Xinyang tablet ameliorates sepsis-induced myocardial dysfunction by regulating Beclin-1 to mediate macrophage autophagy and M2 polarization through LncSICRNT1 targeting E3 ubiquitin ligase TRAF6. Chin Med, 2023, 18(1): 143.

West China Medical Journal

Research progress on ubiquitination modification in sepsis

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