Research progress on endoplasmic reticulum stress signaling pathway in liver diseases_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WANG Liang , ZHOU Ziyi ,  WANG Chaoqun

Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, P. R. China;

Corresponding author：

WANG Chaoqun, Email: wangchq92@tmmu.edu.cn

Keywords：

endoplasmic reticulum stress; non-alcoholic fatty liver disease; hepatocellular carcinoma; hepatic ischemia reperfusion injury; drug induced liver injury

DOI：

10.7507/1007-9424.202412076

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the mechanism of endoplasmic reticulum stress (ERS) in liver diseases. Method We sorted out and summarized the studies related to ERS and liver diseases in recent years. Results Endoplasmic reticulum plays important roles in protein folding, calcium ion storage, and lipid synthesis in cells. Endoplasmic reticulum stress will be induced when the number of misfolded/unfolded proteins in the endoplasmic reticulum increases or the calcium ion homeostasis is unbalanced. The endoplasmic reticulum regulates the unfolded protein response through three transmembrane receptor proteins to initiate corresponding pathways for restoring endoplasmic reticulum homeostasis. Prolonged stress can lead to metabolic disorders. Mild ERS can promote the progression of hepatocellular carcinoma, and continuous ERS will induce cell apoptosis and plays an anti-tumor effect; ERS can promote lipid accumulation in non-alcoholic fatty liver disease and aggravate the progression of the disease; in hepatic ischemia reperfusion injury, ERS activation will aggravate liver damage. Meanwhile, ERS activation plays an important pathogenic role in the pathogenesis of drug-induced liver injury. Conclusion ERS plays a crucial regulatory role in the occurrence and development of liver-related diseases, providing a theoretical basis and new approach for targeted ERS therapy in liver diseases.

1.	Zhou S, Cheng K, Peng Y, et al. Regulation mechanism of endoplasmic reticulum stress on metabolic enzymes in liver diseases. Pharmacol Res, 2024, 207: 107332.
2.	Xiao MC, Jiang N, Chen LL, et al. TRIB3-TRIM8 complex drives NAFLD progression by regulating HNF4α stability. J Hepatol, 2024, 80(5): 778-791.
3.	Andrade-Silva M, Dhillon P, Sanchez-Navarro A, et al. The critical role of endoplasmic reticulum stress and the stimulator of interferon genes (STING) pathway in kidney fibrosis. Kidney Int, 2025, 107(2): 302-316.
4.	Zhao Y, Zheng Y, Li H, et al. Protein folding dependence on selenoprotein M contributes to steady cartilage extracellular matrix repressing ferroptosis via PERK/ATF4/CHAC1 axis. Osteoarthritis Cartilage, 2025, 33(2): 261-275.
5.	Ketkar M, Desai S, Rana P, et al. Inhibition of PERK-mediated unfolded protein response acts as a switch for reversal of residual senescence and as senolytic therapy in glioblastoma. Neuro Oncol, 2024, 26(11): 2027-2043.
6.	Wang C, Shokuhfar T, Klie RF. Precise in situ modulation of local liquid chemistry via electron irradiation in nanoreactors based on graphene liquid cells. Adv Mater, 2016, 28(35): 7716-7722.
7.	Wang W, Li J, Zhou Q. The biological function of cytoplasm-translocated ENDOG (endonuclease G). Autophagy, 2024, 20(2): 445-447.
8.	Duwaerts CC, Siao K, Soon RK, et al. Hepatocyte-specific deletion of XBP1 sensitizes mice to liver injury through hyperactivation of IRE1α. Cell Death Differ, 2021, 28(5): 1455-1465.
9.	Pramanik J, Chen X, Kar G, et al. Genome-wide analyses reveal the IRE1a-XBP1 pathway promotes T helper cell differentiation by resolving secretory stress and accelerating proliferation. Genome Med, 2018, 10(1): 76.
10.	Madhavan A, Kok BP, Rius B, et al. Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity. Nat Commun, 2022, 13(1): 608.
11.	Xu L, Peng F, Luo Q, et al. IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer. Cell, 2024, 187(25): 7248-7266.
12.	Lee EJ, Kim K, Diaz-Aguilar MS, et al. Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome. J Clin Invest, 2025, 135(3): e175562.
13.	Dang TT, Kim MJ, Lee YY, et al. Phosphorylation of EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) is indispensable for nuclear translocation of TFEB and TFE3 during ER stress. Autophagy, 2023, 19(7): 2111-2142.
14.	Wiseman RL, Mesgarzadeh JS, Hendershot LM. Reshaping endoplasmic reticulum quality control through the unfolded protein response. Mol Cell, 2022, 82(8): 1477-1491.
15.	Zhao T, Du J, Zeng H. Interplay between endoplasmic reticulum stress and non-coding RNAs in cancer. J Hematol Oncol, 2020, 13(1): 163.
16.	Auf G, Jabouille A, Guérit S, et al. Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma. Proc Natl Acad Sci U S A, 2010, 107(35): 15553-15558.
17.	Zhang T, Zhao F, Zhang Y, et al. Targeting the IRE1α-XBP1s axis confers selective vulnerability in hepatocellular carcinoma with activated Wnt signaling. Oncogene, 2024, 43(17): 1233-1248.
18.	He L, Li H, Li C, et al. HMMR alleviates endoplasmic reticulum stress by promoting autophagolysosomal activity during endoplasmic reticulum stress-driven hepatocellular carcinoma progression. Cancer Commun (Lond), 2023, 43(9): 981-1002.
19.	Hu C, Xin Z, Sun X, et al. Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate hepatocellular carcinoma metastasis upon endoplasmic reticulum stress. J Exp Clin Cancer Res, 2023, 42(1): 108.
20.	Wu MZ, Fu T, Chen JX, et al. LncRNA GOLGA2P10 is induced by PERK/ATF4/CHOP signaling and protects tumor cells from ER stress-induced apoptosis by regulating Bcl-2 family members. Cell Death Dis, 2020, 11(4): 276.
21.	Hu J, Chen NN, Li LG, et al. Cepharanthine-mediated endoplasmic reticulum stress inhibits Notch1 via binding GRP78 for suppressing hepatocellular carcinoma metastasis. Phytomedicine, 2024, 135: 156162.
22.	Lee SH, Moon HJ, Lee YS, et al. Potentiation of TRAIL-induced cell death by nonsteroidal anti-inflammatory drug in human hepatocellular carcinoma cells through the ER stress-dependent autophagy pathway. Oncol Rep, 2020, 44(3): 1136-1148.
23.	Lin YS, Sun Z, Shen LS, et al. Arnicolide D induces endoplasmic reticulum stress-mediated oncosis via ATF4 and CHOP in hepatocellular carcinoma cells. Cell Death Discov, 2024, 10(1): 134.
24.	Xu Z, Xu J, Sun S, et al. Mecheliolide elicits ROS-mediated ERS driven immunogenic cell death in hepatocellular carcinoma. Redox Biol, 2022, 54: 102351.
25.	Bian M, Fan R, Yang Z, et al. Pt(Ⅱ)-NHC complex induces ROS-ERS-related DAMP balance to harness immunogenic cell death in hepatocellular carcinoma. J Med Chem, 2022, 65(3): 1848-1866.
26.	Yang Z, Bian M, Lv L, et al. Tumor-targeting NHC-Au(Ⅰ) complex induces immunogenic cell death in hepatocellular carcinoma. J Med Chem, 2023, 66(6): 3934-3952.
27.	Boutagy NE, Gamez-Mendez A, Fowler JW, et al. Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice. J Clin Invest, 2024, 134(4): e170453.
28.	Wang T, Wang D, Kuang G, et al. Derlin-1 promotes diet-induced non-alcoholic fatty liver disease via increasing RIPK3-mediated necroptosis. Free Radic Biol Med, 2024, 217: 29-47.
29.	Zhang Z, Qian Q, Li M, et al. The unfolded protein response regulates hepatic autophagy by sXBP1-mediated activation of TFEB. Autophagy, 2021, 17(8): 1841-1855.
30.	Wang W, Tan J, Liu X, et al. Cytoplasmic endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress. Nat Commun, 2023, 14(1): 6201.
31.	Tam AB, Roberts LS, Chandra V, et al. The UPR activator ATF6 responds to proteotoxic and lipotoxic stress by distinct mechanisms. Dev Cell, 2018, 46(3): 327-343. e7.
32.	Kammoun HL, Chabanon H, Hainault I, et al. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest, 2009, 119(5): 1201-1215.
33.	Boslem E, Reibe S, Carlessi R, et al. Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC. Sci Adv, 2023, 9(37): eadh0831.
34.	Weber AA, Yang X, Mennillo E, et al. Lactational delivery of Triclosan promotes non-alcoholic fatty liver disease in newborn mice. Nat Commun, 2022, 13(1): 4346.
35.	Tirosh A, Tuncman G, Calay ES, et al. Intercellular transmission of hepatic ER stress in obesity disrupts systemic metabolism. Cell Metab, 2021, 33(8): 1716.
36.	Teschke R. Microsomal ethanol-oxidizing system: success over 50 years and an encouraging future. Alcohol Clin Exp Res, 2019, 43(3): 386-400.
37.	Cheng Y, Rao P, Li S, et al. Alcohol promotes hepatocyte injury via ER stress sensor XBP1s mediated regulation of autophagy and lysosomal activity. Toxicol Appl Pharmacol, 2024, 492: 117117.
38.	Walter MN, Montoya-Durango D, Rodriguez W, et al. Hepatocyte-specific mitogen-activated protein kinase phosphatase 1 in sexual dimorphism and susceptibility to alcohol induced liver injury. Front Immunol, 2024, 15: 1316228.
39.	Tien S, Zhou H, Zhou Q, et al. PTTG1 alleviates acute alcoholic liver injury by inhibiting endoplasmic reticulum stress-induced hepatocyte pyroptosis. Liver Int, 2023, 43(4): 840-854.
40.	Song Q, Chen Y, Wang J, et al. ER stress-induced upregulation of NNMT contributes to alcohol-related fatty liver development. J Hepatol, 2020, 73(4): 783-793.
41.	Hao L, Zhong W, Dong H, et al. ATF4 activation promotes hepatic mitochondrial dysfunction by repressing NRF1-TFAM signalling in alcoholic steatohepatitis. Gut, 2021, 70(10): 1933-1945.
42.	Nakamura K, Kageyama S, Ito T, et al. Antibiotic pretreatment alleviates liver transplant damage in mice and humans. J Clin Invest, 2019, 129(8): 3420-3434.
43.	Yang Y, Wang P, Zhang C, et al. Hepatocyte-derived MANF alleviates hepatic ischaemia-reperfusion injury via regulating endoplasmic reticulum stress-induced apoptosis in mice. Liver Int, 2021, 41(3): 623-639.
44.	Motiño O, Francés DE, Casanova N, et al. Protective role of hepatocyte cyclooxygenase-2 expression against liver ischemia-reperfusion injury in mice. Hepatology, 2019, 70(2): 650-665.
45.	Rao J, Wang Z, Yu F, et al. XBP1 facilitating NF-κB-p65 nuclear translocation promotes macrophage-originated sterile inflammation via regulating MT2 transcription in the ischemia/reperfusion liver. Cell Mol Gastroenterol Hepatol, 2024, 18(6): 101402.
46.	Li F, Guan Z, Gao Y, et al. ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury. Hepatol Commun, 2024, 8(4): e0399.
47.	Yang C, Wang Z, Hu Y, et al. Hyperglycemia-triggered ATF6-CHOP pathway aggravates acute inflammatory liver injury by β-catenin signaling. Cell Death Discov, 2022, 8(1): 115.
48.	Yang F, Wang S, Liu Y, et al. IRE1α aggravates ischemia reperfusion injury of fatty liver by regulating phenotypic transformation of kupffer cells. Free Radic Biol Med, 2018, 124: 395-407.
49.	Wilson A, McCormick C. Reticulophagy and viral infection. Autophagy, 2025, 21(1): 3-20.
50.	Hossain MG, Ueda K. Regulation of hepatitis B virus replication by modulating endoplasmic reticulum stress (ER-stress). Int J Microbiol, 2024, 2024: 9117453.
51.	Liang Y, Luo X, Schefczyk S, et al. Hepatitis B surface antigen expression impairs endoplasmic reticulum stress-related autophagic flux by decreasing LAMP2. JHEP Rep, 2024, 6(4): 101012.
52.	Shi S, Zhang H, Jiang P, et al. Inhibition of LPCAT3 exacerbates endoplasmic reticulum stress and HBV replication. Int Immunopharmacol, 2024, 143(Pt 2): 113337.
53.	Wang D, Hou C, Cao Y, et al. XBP1 activation enhances MANF expression via binding to endoplasmic reticulum stress response elements within MANF promoter region in hepatitis B. Int J Biochem Cell Biol, 2018, 99: 140-146.
54.	Shu W, Guo Z, Li L, et al. Regulation of molecular chaperone GRP78 by hepatitis B virus: control of viral replication and cell survival. Mol Cell Biol, 2020, 40(3): e00475-419.
55.	Lin D, Chen Y, Koksal AR, et al. Targeting ER stress/PKA/GSK-3β/β-catenin pathway as a potential novel strategy for hepatitis C virus-infected patients. Cell Commun Signal, 2023, 21(1): 102.
56.	Liu L, Ito M, Sakai S, et al. FGF21 upregulation by hepatitis C virus via the eIF2α-ATF4 pathway: implications for interferon signaling suppression and TRIM31-mediated TSC degradation. Front Microbiol, 2024, 15: 1456108.
57.	Tak J, Kim YS, Kim SG. Roles of X-box binding protein 1 in liver pathogenesis. Clin Mol Hepatol, 2025, 31(1): 1-31.
58.	Ren Z, Chen S, Pak S, et al. A mechanism of perhexiline’s cytotoxicity in hepatic cells involves endoplasmic reticulum stress and p38 signaling pathway. Chem Biol Interact, 2021, 334: 109353.
59.	Zhang C, Ge J, Lv M, et al. Selenium prevent cadmium-induced hepatotoxicity through modulation of endoplasmic reticulum-resident selenoproteins and attenuation of endoplasmic reticulum stress. Environ Pollut, 2020, 260: 113873.
60.	Wang J, Ding L, Wang K, et al. Role of endoplasmic reticulum stress in cadmium-induced hepatocyte apoptosis and the protective effect of quercetin. Ecotoxicol Environ Saf, 2022, 241: 113772.
61.	Pang X, Qiao Q, Vonglorkham S, et al. Asiatic acid ameliorates acute hepatic injury by reducing endoplasmic reticulum stress and triggering hepatocyte autophagy. Biomed Pharmacother, 2020, 129: 110375.
62.	Bian M, He J, Jin H, et al. Oroxylin A induces apoptosis of activated hepatic stellate cells through endoplasmic reticulum stress. Apoptosis, 2019, 24(11-12): 905-920.
63.	He E, Ma Y, Kong L, et al. Suppression of endoplasmic reticulum stress-associated pathways and hepatocyte apoptosis participates in the attenuation of betulinic acid on alcohol-provoked liver injury in mice. Food Funct, 2022, 13(22): 11489-11502.
64.	Maiers JL, Malhi H. Endoplasmic reticulum stress in metabolic liver diseases and hepatic fibrosis. Semin Liver Dis, 2019, 39(2): 235-248.
65.	Liao X, Zhan W, Li R, et al. Irisin ameliorates endoplasmic reticulum stress and liver fibrosis through inhibiting PERK-mediated destabilization of HNRNPA1 in hepatic stellate cells. Biol Chem, 2021, 402(6): 703-715.
66.	Zhang X, Zeng Y, Ying H, et al. AdipoRon mitigates liver fibrosis by suppressing serine/glycine biosynthesis through ATF4-dependent glutaminolysis. Ecotoxicol Environ Saf, 2025, 289: 117511.
67.	Wang Q, Zhu X, Li Z, et al. ATF6 promotes liver fibrogenesis by regulating macrophage-derived interleukin-1α expression. Cell Immunol, 2021, 367: 104401.

1. Zhou S, Cheng K, Peng Y, et al. Regulation mechanism of endoplasmic reticulum stress on metabolic enzymes in liver diseases. Pharmacol Res, 2024, 207: 107332.
2. Xiao MC, Jiang N, Chen LL, et al. TRIB3-TRIM8 complex drives NAFLD progression by regulating HNF4α stability. J Hepatol, 2024, 80(5): 778-791.
3. Andrade-Silva M, Dhillon P, Sanchez-Navarro A, et al. The critical role of endoplasmic reticulum stress and the stimulator of interferon genes (STING) pathway in kidney fibrosis. Kidney Int, 2025, 107(2): 302-316.
4. Zhao Y, Zheng Y, Li H, et al. Protein folding dependence on selenoprotein M contributes to steady cartilage extracellular matrix repressing ferroptosis via PERK/ATF4/CHAC1 axis. Osteoarthritis Cartilage, 2025, 33(2): 261-275.
5. Ketkar M, Desai S, Rana P, et al. Inhibition of PERK-mediated unfolded protein response acts as a switch for reversal of residual senescence and as senolytic therapy in glioblastoma. Neuro Oncol, 2024, 26(11): 2027-2043.
6. Wang C, Shokuhfar T, Klie RF. Precise in situ modulation of local liquid chemistry via electron irradiation in nanoreactors based on graphene liquid cells. Adv Mater, 2016, 28(35): 7716-7722.
7. Wang W, Li J, Zhou Q. The biological function of cytoplasm-translocated ENDOG (endonuclease G). Autophagy, 2024, 20(2): 445-447.
8. Duwaerts CC, Siao K, Soon RK, et al. Hepatocyte-specific deletion of XBP1 sensitizes mice to liver injury through hyperactivation of IRE1α. Cell Death Differ, 2021, 28(5): 1455-1465.
9. Pramanik J, Chen X, Kar G, et al. Genome-wide analyses reveal the IRE1a-XBP1 pathway promotes T helper cell differentiation by resolving secretory stress and accelerating proliferation. Genome Med, 2018, 10(1): 76.
10. Madhavan A, Kok BP, Rius B, et al. Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity. Nat Commun, 2022, 13(1): 608.
11. Xu L, Peng F, Luo Q, et al. IRE1α silences dsRNA to prevent taxane-induced pyroptosis in triple-negative breast cancer. Cell, 2024, 187(25): 7248-7266.
12. Lee EJ, Kim K, Diaz-Aguilar MS, et al. Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome. J Clin Invest, 2025, 135(3): e175562.
13. Dang TT, Kim MJ, Lee YY, et al. Phosphorylation of EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) is indispensable for nuclear translocation of TFEB and TFE3 during ER stress. Autophagy, 2023, 19(7): 2111-2142.
14. Wiseman RL, Mesgarzadeh JS, Hendershot LM. Reshaping endoplasmic reticulum quality control through the unfolded protein response. Mol Cell, 2022, 82(8): 1477-1491.
15. Zhao T, Du J, Zeng H. Interplay between endoplasmic reticulum stress and non-coding RNAs in cancer. J Hematol Oncol, 2020, 13(1): 163.
16. Auf G, Jabouille A, Guérit S, et al. Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma. Proc Natl Acad Sci U S A, 2010, 107(35): 15553-15558.
17. Zhang T, Zhao F, Zhang Y, et al. Targeting the IRE1α-XBP1s axis confers selective vulnerability in hepatocellular carcinoma with activated Wnt signaling. Oncogene, 2024, 43(17): 1233-1248.
18. He L, Li H, Li C, et al. HMMR alleviates endoplasmic reticulum stress by promoting autophagolysosomal activity during endoplasmic reticulum stress-driven hepatocellular carcinoma progression. Cancer Commun (Lond), 2023, 43(9): 981-1002.
19. Hu C, Xin Z, Sun X, et al. Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate hepatocellular carcinoma metastasis upon endoplasmic reticulum stress. J Exp Clin Cancer Res, 2023, 42(1): 108.
20. Wu MZ, Fu T, Chen JX, et al. LncRNA GOLGA2P10 is induced by PERK/ATF4/CHOP signaling and protects tumor cells from ER stress-induced apoptosis by regulating Bcl-2 family members. Cell Death Dis, 2020, 11(4): 276.
21. Hu J, Chen NN, Li LG, et al. Cepharanthine-mediated endoplasmic reticulum stress inhibits Notch1 via binding GRP78 for suppressing hepatocellular carcinoma metastasis. Phytomedicine, 2024, 135: 156162.
22. Lee SH, Moon HJ, Lee YS, et al. Potentiation of TRAIL-induced cell death by nonsteroidal anti-inflammatory drug in human hepatocellular carcinoma cells through the ER stress-dependent autophagy pathway. Oncol Rep, 2020, 44(3): 1136-1148.
23. Lin YS, Sun Z, Shen LS, et al. Arnicolide D induces endoplasmic reticulum stress-mediated oncosis via ATF4 and CHOP in hepatocellular carcinoma cells. Cell Death Discov, 2024, 10(1): 134.
24. Xu Z, Xu J, Sun S, et al. Mecheliolide elicits ROS-mediated ERS driven immunogenic cell death in hepatocellular carcinoma. Redox Biol, 2022, 54: 102351.
25. Bian M, Fan R, Yang Z, et al. Pt(Ⅱ)-NHC complex induces ROS-ERS-related DAMP balance to harness immunogenic cell death in hepatocellular carcinoma. J Med Chem, 2022, 65(3): 1848-1866.
26. Yang Z, Bian M, Lv L, et al. Tumor-targeting NHC-Au(Ⅰ) complex induces immunogenic cell death in hepatocellular carcinoma. J Med Chem, 2023, 66(6): 3934-3952.
27. Boutagy NE, Gamez-Mendez A, Fowler JW, et al. Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice. J Clin Invest, 2024, 134(4): e170453.
28. Wang T, Wang D, Kuang G, et al. Derlin-1 promotes diet-induced non-alcoholic fatty liver disease via increasing RIPK3-mediated necroptosis. Free Radic Biol Med, 2024, 217: 29-47.
29. Zhang Z, Qian Q, Li M, et al. The unfolded protein response regulates hepatic autophagy by sXBP1-mediated activation of TFEB. Autophagy, 2021, 17(8): 1841-1855.
30. Wang W, Tan J, Liu X, et al. Cytoplasmic endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress. Nat Commun, 2023, 14(1): 6201.
31. Tam AB, Roberts LS, Chandra V, et al. The UPR activator ATF6 responds to proteotoxic and lipotoxic stress by distinct mechanisms. Dev Cell, 2018, 46(3): 327-343. e7.
32. Kammoun HL, Chabanon H, Hainault I, et al. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest, 2009, 119(5): 1201-1215.
33. Boslem E, Reibe S, Carlessi R, et al. Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC. Sci Adv, 2023, 9(37): eadh0831.
34. Weber AA, Yang X, Mennillo E, et al. Lactational delivery of Triclosan promotes non-alcoholic fatty liver disease in newborn mice. Nat Commun, 2022, 13(1): 4346.
35. Tirosh A, Tuncman G, Calay ES, et al. Intercellular transmission of hepatic ER stress in obesity disrupts systemic metabolism. Cell Metab, 2021, 33(8): 1716.
36. Teschke R. Microsomal ethanol-oxidizing system: success over 50 years and an encouraging future. Alcohol Clin Exp Res, 2019, 43(3): 386-400.
37. Cheng Y, Rao P, Li S, et al. Alcohol promotes hepatocyte injury via ER stress sensor XBP1s mediated regulation of autophagy and lysosomal activity. Toxicol Appl Pharmacol, 2024, 492: 117117.
38. Walter MN, Montoya-Durango D, Rodriguez W, et al. Hepatocyte-specific mitogen-activated protein kinase phosphatase 1 in sexual dimorphism and susceptibility to alcohol induced liver injury. Front Immunol, 2024, 15: 1316228.
39. Tien S, Zhou H, Zhou Q, et al. PTTG1 alleviates acute alcoholic liver injury by inhibiting endoplasmic reticulum stress-induced hepatocyte pyroptosis. Liver Int, 2023, 43(4): 840-854.
40. Song Q, Chen Y, Wang J, et al. ER stress-induced upregulation of NNMT contributes to alcohol-related fatty liver development. J Hepatol, 2020, 73(4): 783-793.
41. Hao L, Zhong W, Dong H, et al. ATF4 activation promotes hepatic mitochondrial dysfunction by repressing NRF1-TFAM signalling in alcoholic steatohepatitis. Gut, 2021, 70(10): 1933-1945.
42. Nakamura K, Kageyama S, Ito T, et al. Antibiotic pretreatment alleviates liver transplant damage in mice and humans. J Clin Invest, 2019, 129(8): 3420-3434.
43. Yang Y, Wang P, Zhang C, et al. Hepatocyte-derived MANF alleviates hepatic ischaemia-reperfusion injury via regulating endoplasmic reticulum stress-induced apoptosis in mice. Liver Int, 2021, 41(3): 623-639.
44. Motiño O, Francés DE, Casanova N, et al. Protective role of hepatocyte cyclooxygenase-2 expression against liver ischemia-reperfusion injury in mice. Hepatology, 2019, 70(2): 650-665.
45. Rao J, Wang Z, Yu F, et al. XBP1 facilitating NF-κB-p65 nuclear translocation promotes macrophage-originated sterile inflammation via regulating MT2 transcription in the ischemia/reperfusion liver. Cell Mol Gastroenterol Hepatol, 2024, 18(6): 101402.
46. Li F, Guan Z, Gao Y, et al. ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury. Hepatol Commun, 2024, 8(4): e0399.
47. Yang C, Wang Z, Hu Y, et al. Hyperglycemia-triggered ATF6-CHOP pathway aggravates acute inflammatory liver injury by β-catenin signaling. Cell Death Discov, 2022, 8(1): 115.
48. Yang F, Wang S, Liu Y, et al. IRE1α aggravates ischemia reperfusion injury of fatty liver by regulating phenotypic transformation of kupffer cells. Free Radic Biol Med, 2018, 124: 395-407.
49. Wilson A, McCormick C. Reticulophagy and viral infection. Autophagy, 2025, 21(1): 3-20.
50. Hossain MG, Ueda K. Regulation of hepatitis B virus replication by modulating endoplasmic reticulum stress (ER-stress). Int J Microbiol, 2024, 2024: 9117453.
51. Liang Y, Luo X, Schefczyk S, et al. Hepatitis B surface antigen expression impairs endoplasmic reticulum stress-related autophagic flux by decreasing LAMP2. JHEP Rep, 2024, 6(4): 101012.
52. Shi S, Zhang H, Jiang P, et al. Inhibition of LPCAT3 exacerbates endoplasmic reticulum stress and HBV replication. Int Immunopharmacol, 2024, 143(Pt 2): 113337.
53. Wang D, Hou C, Cao Y, et al. XBP1 activation enhances MANF expression via binding to endoplasmic reticulum stress response elements within MANF promoter region in hepatitis B. Int J Biochem Cell Biol, 2018, 99: 140-146.
54. Shu W, Guo Z, Li L, et al. Regulation of molecular chaperone GRP78 by hepatitis B virus: control of viral replication and cell survival. Mol Cell Biol, 2020, 40(3): e00475-419.
55. Lin D, Chen Y, Koksal AR, et al. Targeting ER stress/PKA/GSK-3β/β-catenin pathway as a potential novel strategy for hepatitis C virus-infected patients. Cell Commun Signal, 2023, 21(1): 102.
56. Liu L, Ito M, Sakai S, et al. FGF21 upregulation by hepatitis C virus via the eIF2α-ATF4 pathway: implications for interferon signaling suppression and TRIM31-mediated TSC degradation. Front Microbiol, 2024, 15: 1456108.
57. Tak J, Kim YS, Kim SG. Roles of X-box binding protein 1 in liver pathogenesis. Clin Mol Hepatol, 2025, 31(1): 1-31.
58. Ren Z, Chen S, Pak S, et al. A mechanism of perhexiline’s cytotoxicity in hepatic cells involves endoplasmic reticulum stress and p38 signaling pathway. Chem Biol Interact, 2021, 334: 109353.
59. Zhang C, Ge J, Lv M, et al. Selenium prevent cadmium-induced hepatotoxicity through modulation of endoplasmic reticulum-resident selenoproteins and attenuation of endoplasmic reticulum stress. Environ Pollut, 2020, 260: 113873.
60. Wang J, Ding L, Wang K, et al. Role of endoplasmic reticulum stress in cadmium-induced hepatocyte apoptosis and the protective effect of quercetin. Ecotoxicol Environ Saf, 2022, 241: 113772.
61. Pang X, Qiao Q, Vonglorkham S, et al. Asiatic acid ameliorates acute hepatic injury by reducing endoplasmic reticulum stress and triggering hepatocyte autophagy. Biomed Pharmacother, 2020, 129: 110375.
62. Bian M, He J, Jin H, et al. Oroxylin A induces apoptosis of activated hepatic stellate cells through endoplasmic reticulum stress. Apoptosis, 2019, 24(11-12): 905-920.
63. He E, Ma Y, Kong L, et al. Suppression of endoplasmic reticulum stress-associated pathways and hepatocyte apoptosis participates in the attenuation of betulinic acid on alcohol-provoked liver injury in mice. Food Funct, 2022, 13(22): 11489-11502.
64. Maiers JL, Malhi H. Endoplasmic reticulum stress in metabolic liver diseases and hepatic fibrosis. Semin Liver Dis, 2019, 39(2): 235-248.
65. Liao X, Zhan W, Li R, et al. Irisin ameliorates endoplasmic reticulum stress and liver fibrosis through inhibiting PERK-mediated destabilization of HNRNPA1 in hepatic stellate cells. Biol Chem, 2021, 402(6): 703-715.
66. Zhang X, Zeng Y, Ying H, et al. AdipoRon mitigates liver fibrosis by suppressing serine/glycine biosynthesis through ATF4-dependent glutaminolysis. Ecotoxicol Environ Saf, 2025, 289: 117511.
67. Wang Q, Zhu X, Li Z, et al. ATF6 promotes liver fibrogenesis by regulating macrophage-derived interleukin-1α expression. Cell Immunol, 2021, 367: 104401.

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