细胞死亡在酒精相关性肝病中的作用及天然产物调控机制研究进展

Research progress in the regulation of cell death in alcohol-associated liver disease: regulatory roles of natural products

摘要

酒精相关性肝病(alcohol-associated liver disease,ALD)是由于长期过量饮酒而引起的一系列肝脏疾病的总称,涵盖了一系列病理进程,如酒精性脂肪肝、酒精性肝炎、酒精性肝纤维化等。ALD病程复杂,发病过程中涉及多种细胞死亡方式。大量研究表明,程序性细胞死亡(programmed cell death,PCD)密切参与了ALD的病理进程,研究细胞死亡的调控对ALD的机制研究至关重要。本文系统梳理了近年来细胞死亡在ALD中的作用机制,以及天然产物通过调控细胞死亡途径改善ALD的机制研究进展,以期为后续ALD发病机制研究和天然产物防治ALD及相关临床治疗药物开发提供理论依据。

Abstract

Alcohol-associated liver disease (ALD) is a spectrum of disorders in which the liver is damaged due to prolonged heavy alcohol consumption, including simple fatty liver disease, alcoholic hepatitis, alcoholic liver fibrosis, and cirrhosis. The progression of ALD is complex, and various types of cell death are involved. Numerous studies have shown that programmed cell death (PCD) plays a crucial role in the pathological processes of ALD, thus studying the regulation of cell death is essential for understanding the underlying mechanisms of ALD. In this review, recent research progress of the regulatory mechanisms of cell death in ALD were discussed. And the mechanism role of natural products in improving ALD via regulating PCD was systematically reviewed, aiming to provide the basis and clues for the subsequent investigations of ALD pathogenesis and further clinical development and application of natural products in the treatment of ALD.

关键词

细胞死亡 / 酒精相关性肝病 / 作用机制 / 天然产物 / 研究进展

Key words

cell death / alcohol-associated liver disease / mechanism / natural product / research progress

参考文献

[1] MACKOWIAK B, FU Y, MACCIONI L, et al. Alcohol-associated liver disease[J]. J Clin Invest, 2024, 134(3): e176345.

[2] AMONKER S, HOUSHMAND A, HINKSON A, et al. Prevalence of alcohol-associated liver disease: a systematic review and meta-analysis[J]. Hepatol Commun, 2023, 7(5): e0133.

[3] XU H, XIAO P, ZHANG F, et al. Epidemic characteristics of alcohol related liver disease in Asia from 2000 to 2020: a systematic review and meta-analysis[J]. Liver Int, 2022, 42(9): 1991-1998.

[4] WU X, MIYATA T, et al. Recent advances in understanding of pathogenesis of alcohol-associated liver disease[J]. Annu Rev Pathol, 2023, 18: 411-438.

[5] YUAN J, OFENGHEIM D. A guide to cell death pathways[J]. Nat Rev Mol Cell Biol, 2024, 25(5): 379-395.

[6] HYUN J, HAN J, LEE C, et al. Pathophysiological aspects of alcohol metabolism in the liver[J]. Int J Mol Sci, 2021, 22(11): 5717.

[7] LIU S Y, TSAI I T, HSU Y C. Alcohol-related liver disease: basic mechanisms and clinical perspectives[J]. Int J Mol Sci, 2021, 22(10): 5170.

[8] CHEN D, GUO Z, YAO L, et al. Targeting oxidative stress-mediated regulated cell death as a vulnerability in cancer[J]. Redox Biol, 2025, 84: 103686.

[9] KALE J, OSTERLUND E J, ANDREWS D W. BCL-2 family proteins: changing partners in the dance towards death[J]. Cell Death Differ, 2018, 25(1): 65-80.

[10] NEWTON K, STRASSER A, KAYAGAKI N, et al. Cell death[J]. Cell, 2024, 187(2): 235-256.

[11] NAGY L E, DING W X, CRESCI G, et al. Linking pathogenic mechanisms of alcoholic liver disease with clinical phenotypes[J]. Gastroenterology, 2016, 150(8): 1756-1768.

[12] SANZ-GARCIA C, POULSEN K L, BELLOS D, et al. The non-transcriptional activity of IRF3 modulates hepatic immune cell populations in acute-on-chronic ethanol administration in mice[J]. J Hepatol, 2019, 70(5): 974-984.

[13] LUTHER J, KHAN S, GALAM K, et al. Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation[J]. Proc Natl Acad Sci USA, 2020, 117(21): 11667-11673.

[14] YAN C, HU W, TU J, et al. Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease[J]. J Transl Med, 2023, 21(1): 300.

[15] YAN J, WAN P, CHOKSI S, et al. Necroptosis and tumor progression[J]. Trends Cancer, 2022, 8(1): 21-27.

[16] ZHOU Y, WU R, WANG X, et al. Roles of necroptosis in alcoholic liver disease and hepatic pathogenesis[J]. Cell Prolif, 2022, 55(3): e13193.

[17] ZHANG Z, XIE G, LIANG G, et al. RIPK3-mediated necroptosis and neutrophil infiltration are associated with poor prognosis in patients with alcoholic cirrhosis[J]. J Immunol Res, 2018, 2018: 1509851.

[18] MIYATA T, WU X, FAN X, et al. Differential role of MLKL in alcohol-associated and non-alcohol-associated fatty liver diseases in mice and humans[J]. JCI Insight, 2021, 6(4): e140180.

[19] ORTEGA-RIBERA M, ZHUANG Y, BABUTA M, et al. A novel multi-organ male model of alcohol-induced acute-on-chronic liver failure reveals NET-mediated hepatocellular death, which is prevented by RIPK3 inhibition[J]. Cell Mol Gastroenterol Hepatol, 2025, 19(4): 101446.

[20] ROCHETTE L, DOGON G, RIGAL E, et al. Lipid peroxidation and iron metabolism: two cornerstones in the homeostasis control of ferroptosis[J]. Int J Mol Sci, 2022, 24(1): 449.

[21] LI K Y, WU X M, LUO M, et al. Research progress of traditional Chinese medicine regulating ferroptosis in the treatment of liver cancer[J]. Journal of Shenyang Pharmaceutical University(沈阳药科大学学报), 2025, 42(7): 600-607.

[22] SHI J F, LIU Y, WANG Y, et al. Targeting ferroptosis, a novel programmed cell death, for the potential of alcohol-related liver disease therapy[J]. Front Pharmacol, 2023, 14: 1194343.

[23] FERRAO K, ALI N, MEHTA K J. Iron and iron-related proteins in alcohol consumers: cellular and clinical aspects[J]. J Mol Med (Berl), 2022, 100(12): 1673-1689.

[24] LI L X, GUO F F, LIU H, et al. Iron overload in alcoholic liver disease: underlying mechanisms, detrimental effects, and potential therapeutic targets[J]. Cell Mol Life Sci, 2022, 79(4): 201.

[25] WANG M, WEN X, FENG Z, et al. ACSS2 protects against alcohol-induced hepatocyte ferroptosis through regulation of hepcidin expression[J]. Nat Commun, 2025, 16(1): 5491.

[26] ZHOU Z, YE T J, DECARO E, et al. Intestinal SIRT1 deficiency protects mice from ethanol-induced liver injury by mitigating ferroptosis[J]. Am J Pathol, 2020, 190(1): 82-92.

[27] XUE M, TIAN Y, SUI Y, et al. Protective effect of fucoidan against iron overload and ferroptosis-induced liver injury in rats exposed to alcohol[J]. Biomed Pharmacother, 2022, 153: 113402.

[28] VASUDEVAN S O, BEHL B, RATHINAM V A. Pyroptosis-induced inflammation and tissue damage[J]. Semin Immunol, 2023, 69: 101781.

[29] BRAVO F J, MENA J, MEJÍA REYES Á, et al. The impact of Panx1 on inflammation, immunity, and cancer: a comprehensive review[J]. Front Med (Lausanne), 2025, 12: 1572418.

[30] LIU Z, BUSSCHER B M, STORL-DESMOND M, et al. Mechanisms of gasdermin recognition by proteases[J]. J Mol Biol, 2022, 434(4): 167274.

[31] PETRASEK J, BALA S, CSAK T, et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice[J]. J Clin Invest, 2012, 122(10): 3476-3489.

[32] PETRASEK J, IRACHETA-VELLVE A, SAHA B, et al. Metabolic danger signals, uric acid and ATP, mediate inflammatory cross-talk between hepatocytes and immune cells in alcoholic liver disease[J]. J Leukoc Biol, 2015, 98(2): 249-256.

[33] XIE Y, WANG Z, SONG G, et al. GSDMD induces hepatocyte pyroptosis to trigger alcoholic hepatitis through modulating mitochondrial dysfunction[J]. Cell Div, 2024, 19(1): 10.

[34] SAYAF K, BATTISTELLA S, RUSSO F P. NLRP3 inflammasome in acute and chronic liver diseases[J]. Int J Mol Sci, 2024, 25(8): 4537.

[35] HEO M J, KIM T H, YOU J S, et al. Alcohol dysregulates miR-148a in hepatocytes through FoxO1, facilitating pyroptosis via TXNIP overexpression[J]. Gut, 2019, 68(4): 708-720.

[36] NAH J, ZABLOCKI D, SADOSHIMA J. Autosis: a new target to prevent cell death[J]. JACC Basic Transl Sci, 2020, 5(8): 857-869.

[37] WANG Y, LIU Z, SHU S, et al. AMPK/mTOR signaling in autophagy regulation during cisplatin-induced acute kidney injury[J]. Front Physiol, 2020, 11: 619730.

[38] BARNABA C, BROADBENT D G, KAMINSKY E G, et al. AMPK regulates phagophore-to-autophagosome maturation[J]. J Cell Biol, 2024, 223(8): e202309145.

[39] LIU S, YAO S, YANG H, et al. Autophagy: regulator of cell death[J]. Cell Death Dis, 2023, 14(10): 648.

[40] DING W X, LI M, CHEN X, et al. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice[J]. Gastroenterology, 2010, 139(5): 1740-1752.

[41] YUAN F, XU Y, YOU K, et al. Calcitriol alleviates ethanol-induced hepatotoxicity via AMPK/mTOR-mediated autophagy[J]. Arch Biochem Biophys, 2021, 697: 108694.

[42] ZHANG J, PING J, JIANG N, et al. Resveratrol inhibits hepatic stellate cell activation by regulating autophagy and apoptosis through the SIRT1 and JNK signaling pathways[J]. J Food Biochem, 2022, 46(12): e14463.

[43] DIFAZIO P, MATROOD S. Targeting autophagy in liver cancer[J]. Transl Gastroenterol Hepatol, 2018, 3: 39.

[44] SONG H S, JANG S, KANG S C. Bavachalcone from Cullen corylifolium induces apoptosis and autophagy in HepG2 cells[J]. Phytomedicine, 2018, 40: 37-47.

[45] 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[J]. Food Funct, 2022, 13(22): 11489-11502.

[46] HE E, MA Y, KONG L, et al. Ursolic acid reduces hepatocellular apoptosis and alleviates alcohol-induced liver injury via irreversible inhibition of CASP3 in vivo[J]. Acta Pharmacol Sin, 2021, 42(7): 1101-1110.

[47] WANG M, ZHANG F, ZHOU J, et al. Glabridin ameliorates alcohol-caused liver damage by reducing oxidative stress and inflammation via p38 MAPK/Nrf2/NF-κB pathway[J]. Nutrients, 2023, 15(9): 2157.

[48] JIANG Z B, GAO J, CHAI Y H, et al. Astragaloside alleviates alcoholic fatty liver disease by suppressing oxidative stress[J]. Kaohsiung J Med Sci, 2021, 37(8): 718-729.

[49] LI J, YANG C, ZHANG S, et al. Ginsenoside Rg1 inhibits inflammatory responses via modulation of the nuclear factor κB pathway and inhibition of inflammasome activation in alcoholic hepatitis[J]. Int J Mol Med, 2018, 41(2): 899-907.

[50] ZHOU Y, JIN H, WU Y, et al. Gallic acid protects against ethanol-induced hepatocyte necroptosis via an NRF2-dependent mechanism[J]. Toxicol In Vitro, 2019, 57: 226-232.

[51] HAO J, HU R, ZHAO J, et al. Metabolomics combined with network pharmacology reveals the protective effect of astragaloside IV on alcoholic liver disease[J]. Phytomedicine, 2024, 135: 156032.

[52] LU C, XU W, ZHANG F, et al. Nrf2 knockdown disrupts the protective effect of curcumin on alcohol-induced hepatocyte necroptosis[J]. Mol Pharm, 2016, 13(12): 4043-4053.

[53] SHAO Y, WANG X, ZHOU Y, et al. Pterostilbene attenuates RIPK3-dependent hepatocyte necroptosis in alcoholic liver disease via SIRT2-mediated NFATc4 deacetylation[J]. Toxicology, 2021, 461: 152923.

[54] ZHOU L, XIAO M, LI Y, et al. Ursolic acid ameliorates alcoholic liver injury through attenuating oxidative stress-mediated ferroptosis and modulating gut microbiota[J]. J Agric Food Chem, 2024, 72(38): 21181-21192.

[55] LIU D D, ZENG Y, MENG T, et al. Isorhamnetin alleviates acute liver injury by blocking ferroptosis[J]. Chem Eng J, 2025, 525: 169760.

[56] REN Y, DENG F, ZHU H, et al. Effect of epigallocatechin-3-gallate on iron overload in mice with alcoholic liver disease[J]. Mol Biol Rep, 2011, 38(2): 879-886.

[57] LI X, LIU L, WAN M X, et al. Active Components of Pueraria lobata through the MAPK/ERK signaling pathway alleviate iron overload in alcoholic liver disease[J]. Chem Biodivers, 2024, 21(5): e202400005.

[58] LI Y, CHEN M, XU Y, et al. Iron-mediated lysosomal membrane permeabilization in ethanol-induced hepatic oxidative damage and apoptosis: protective effects of quercetin[J]. Oxid Med Cell Longev, 2016, 2016: 4147610.

[59] TANG Y, LI Y, YU H, et al. Quercetin prevents ethanol-induced iron overload by regulating hepcidin through the BMP6/SMAD4 signaling pathway[J]. J Nutr Biochem, 2014, 25(6): 675-682.

[60] ZHAO X, WANG C, DAI S, et al. Quercetin protects ethanol-induced hepatocyte pyroptosis via scavenging mitochondrial ROS and promoting PGC-1-regulated mitochondrial homeostasis in L02 cells[J]. Oxid Med Cell Longev, 2022, 2022: 4591134.

[61] ZHANG X, DONG Z, FAN H, et al. Scutellarin prevents acute alcohol-induced liver injury via inhibiting oxidative stress by regulating the Nrf2/HO-1 pathway and inhibiting inflammation by regulating the AKT, p38 MAPK/NF-κB pathways[J]. J Zhejiang Univ-Sc B, 2023, 24(7): 617-631.

[62] JIN Y, WANG C, MENG Z, et al. Proanthocyanidins alleviate acute alcohol liver injury by inhibiting pyroptosis via inhibiting the ROS-MLKL-CTSB-NLRP3 pathway[J]. Phytomedicine, 2025, 136: 156268.

[63] SHANG Y, JIANG M, CHEN N, et al. Inhibition of HMGB1/TLR4 signaling pathway by digitoflavone: a potential therapeutic role in alcohol-associated liver disease[J]. J Agric Food Chem, 2022, 70(9): 2968-2983.

[64] KAI J, YANG X, WANG Z, et al. Oroxylin A promotes PGC-1α/Mfn2 signaling to attenuate hepatocyte pyroptosis via blocking mitochondrial ROS in alcoholic liver disease[J]. Free Radic Biol Med, 2020, 153: 89-102.

[65] ZHANG J J, ZHONG J T, WANG W L, et al. Embelin improves alcoholic steatohepatitis in alcohol-associated liver disease via ATF6-mediated P2X7r-NLRP3 signaling pathway[J]. Phytomedicine, 2025, 140: 156638.

[66] ZUO R M, JIAO J Y, CHEN N, et al. Carnosic acid suppressed the formation of NETs in alcoholic hepatosteatosis based on P2X7R-NLRP3 axis[J]. Phytomedicine, 2023, 110: 154599.

[67] MA Y, DING Q, QIAN Q, et al. AMPK-regulated autophagy contributes to ursolic acid supplementation-alleviated hepatic steatosis and liver injury in chronic alcohol-fed mice[J]. ACS Omega, 2022, 8(1): 907-914.

[68] JIANG Y, ZHOU Y, XU W, et al. Induction of Sestrin2 by pterostilbene suppresses ethanol-triggered hepatocyte senescence by degrading CCN1 via p62-dependent selective autophagy[J]. Cell Biol Toxicol, 2023, 39(3): 729-749.

[69] TANG L, YANG F, FANG Z, et al. Resveratrol ameliorates alcoholic fatty liver by inducing autophagy[J]. Am J Chin Med, 2016, 44(6): 1207-1220.

[70] ZHANG J, PING J, JIANG N, et al. Resveratrol inhibits hepatic stellate cell activation by regulating autophagy and apoptosis through the SIRT1 and JNK signaling pathways[J]. J Food Biochem, 2022, 46(12): e14463.

[71] TAN Y, LI C, ZHOU J, et al. Berberine attenuates liver fibrosis by autophagy inhibition triggering apoptosis via the miR-30a-5p/ATG5 axis[J]. Exp Cell Res, 2023, 427(2): 113600.

[72] SHUI L, WANG W, XIE M, et al. Isoquercitrin induces apoptosis and autophagy in hepatocellular carcinoma cells via AMPK/mTOR/p70S6K signaling pathway[J]. Aging, 2020, 12: 24318-24332.

[73] SONG H S, JANG S, KANG S C. Bavachalcone from Cullen corylifolium induces apoptosis and autophagy in HepG2 cells[J]. Phytomedicine, 2018, 40: 37-47.

[74] LI J, WANG Y, WU Z, et al. Identification of diagnostic markers and molecular clusters of cuproptosis-related genes in alcohol-related liver disease based on machine learning and experimental validation[J]. Heliyon, 2024, 10(18): e37612.

[75] QIN Q, CHEN W, KING C D, et al. The critical role of the ZBP1-NINJ1 axis and IRF1/IRF9 in ethanol-induced cell death, PANoptosis, and alcohol-associated liver disease[J]. bioRxiv, 2025, 03.12.642836.

[76] KASPER P, LANG S, STEFFEN H M, et al. Management of alcoholic hepatitis: a clinical perspective[J]. Liver Int, 2023, 43(10): 2078-2095.

[77] AYARES G, IDALSOAGA F, DÍAZ L A, et al. Current medical treatment for alcohol-associated liver disease[J]. J Clin Exp Hepatol, 2022, 12(5): 1333-1348.

[78] WANG Y, YUAN M, LI S, et al. Multifunctional liposome delivery system based on ursodeoxycholic acid sodium for the encapsulation of silibinin and combined treatment of alcoholic liver injury[J]. Mol Pharm, 2025, 22(3): 1480-1497.

[79] HAO S, WANG Y, LYU Y, et al. A hepatocyte targeted silymarin sea cucumber peptide-galactose nanoparticle for the alleviation of ethanol-induced damage in cells[J]. Colloids Surf B Biointerfaces, 2025, 257: 115152.

[80] WANG F, LIU Y, CAI P, et al. Fabrication and characterization of gelatin-finger citron polysaccharide nanoparticles for enhanced solubility and bioavailability of luteolin in treating acute alcoholic liver disease[J]. J Agric Food Chem, 2024, 72(50): 28072-28083.

基金资助

国家自然科学基金资助项目(82004062)