脂质代谢紊乱与药物性肝损伤的关联机制及研究现况

doi:10.16138/j.1673-6087.2026.02.01

摘要/Abstract

摘要：

药物性肝损伤（drug-induced liver injury, DILI）是临床常见的、具有高度异质性的药物不良反应。其中，药物性脂肪肝（drug-induced fatty liver disease，DIFLD）是以肝细胞脂质异常蓄积为主要表型的一种特殊类型。与此同时，已存在的代谢功能障碍相关脂肪性肝病（metabolic dysfunction-associated steatotic liver disease，MASLD）又可作为易感背景，增加其发生风险，并影响临床转归。因此，DIFLD与MASLD基础上的DILI既相互关联，又具有不同的病理基础和临床特征。现有研究表明，二者的发生、发展均涉及线粒体功能障碍、核受体及转录调控异常、脂质合成与输出失衡、氧化应激及炎症激活等发病机制。本文就脂质代谢紊乱与DILI的流行病学特征、交互作用机制及临床转归进行综述，以期为高危人群识别、个体化用药及新药安全性评价提供依据。

关键词: 脂质代谢紊乱, 药物性肝损伤, 药物性脂肪肝, 代谢功能障碍相关脂肪性肝病, 临床转归

Abstract:

Drug-induced liver injury (DILI) is a common and highly heterogeneous adverse drug reaction in clinical practice. Drug-induced fatty liver disease (DIFLD) is a distinct subtype of DILI characterized primarily by abnormal hepatic lipid accumulation. Meanwhile, pre-existing metabolic dysfunction-associated steatotic liver disease (MASLD) may serve as a susceptible background that increases the risk of DILI and influences clinical outcomes. Accordingly, DIFLD and DILI occurring in the setting of MASLD are related, while differing in their pathologic basis and clinical features. Current research suggests that the development and progression of both reactions involve multiple mechanisms, including mitochondrial dysfunction, dysregulation of nuclear receptors and transcriptional control, imbalance between lipid synthesis and export, oxidative stress, and activation of inflammatory pathways. This article reviews the epidemiologic characteristics, interaction mechanisms, and clinical outcomes associated with lipid metabolism disorders and DILI, with the aim of providing a basis for identification of high-risk populations, individualized drug therapy, and safety evaluation of new drugs.

Key words: lipid metabolism disorders, drug-induced liver injury, drug-induced fatty liver disease, metabolic dysfunction-associated steatotic liver disease, clinical outcomes

赖荣陶, 娄玮蒨. 脂质代谢紊乱与药物性肝损伤的关联机制及研究现况[J]. 内科理论与实践, 2026, 21(02): 107-112.

LAI Rongtao, LOU Weiqian. Mechanisms and research progress of the association between lipid metabolism disorders and drug-induced liver injury[J]. Journal of Internal Medicine Concepts & Practice, 2026, 21(02): 107-112.

图/表 1

表1

DIFLD与MASLD背景下DILI的特征比较

疾病名称	DIFLD	MASLD背景的DILI
ALT：丙氨酸转氨酶（alanine aminotransferase）；AST：天冬氨酸转氨酶（aspartate transferase）；INR：国际标准化比值(international normalized ratio)； DISH：药物性脂肪性肝炎（drug-induced steatohepatitis）；RUCAM：Roussel Uclaf 因果关系评估法(Roussel Uclaf Causality Assessment Method)； *：提示这些药物在两种疾病状态下都可加剧脂质代谢紊乱。
定义	药物直接导致肝细胞脂质异常蓄积	在既往MASLD基础上药物诱发或加重的肝损伤
基础肝脏状态	可发生于无明确脂肪肝患者，也可叠加于代谢异常者	既往MASLD及合并代谢危险因素
主要机制	药物直接干扰脂质代谢关键环节包括线粒体功能障碍、脂肪酸β-氧化受抑、核受体/转录调控异常、脂质合成增加及VLDL输出受阻，并可继发氧化应激和炎症激活	既往MASLD已存在线粒体功能障碍、核受体/转录调控异常、脂质合成-氧化-输出失衡、氧化应激及慢性低度炎症。药物在此脂质代谢紊乱的基础上进一步加重线粒体损伤、促进氧化反应和炎症放大，诱发或加重DILI
病理特点	以大泡性脂肪变常见；小泡性脂肪变提示较强线粒体毒性	在MASLD/MASH样病变基础上叠加DILI表现，可见脂肪变、气球样变、小叶炎症、坏死、胆汁淤积或混合性损伤
临床特征	早期多无症状或仅乏力	早期多无特异性症状，或仅表现为乏力
实验室表现	ALT/AST多为轻-中度升高，单纯脂肪变时胆红素常不高	可呈肝细胞型、胆汁淤积型或混合型损伤，胆红素和INR升高提示病情进展
潜伏期	多为数周至数月，部分与累积剂量相关	因药物而异，数天至数月
诊断关键	明确脂肪变性药物暴露史及停药后症状是否改善	明确MASLD背景、药物因果关系并排除其他病因，可结合RUCAM因果评估量表
影像与活检	影像可发现脂肪肝，但难定病因；活检有助于判断脂肪变性类型、程度	影像难区分MASLD进展与叠加DILI；活检适用于诊断不清、停药后仍有进展者
临床转归	单纯性脂肪变性多可逆，若进展为DISH或纤维化，则预后较差	受MASLD严重程度的影响，MASLD损伤程度越重，越容易导致重症及不良临床转归
常见药物	胺碘酮、哌克昔林、丙戊酸、四环素、他莫昔芬^、甲氨蝶呤^、糖皮质激素^、雌激素、5-氟尿嘧啶、非甾体抗炎药^、齐多夫定^、抗逆转录病毒药/核苷类逆转录酶抑制剂^、伊立替康^*、卡马西平	他莫昔芬、甲氨蝶呤、伊立替康、5-氟尿嘧啶、糖皮质激素、抗逆转录病毒药/核苷类逆转录酶抑制剂、对乙酰氨基酚、哌拉西林-他唑巴坦。

表1

参考文献 37

[1]	López-Pascual E, Rienda I, Perez-Rojas J, et al. Drug-induced fatty liver disease (DIFLD): a comprehensive analysis of clinical, biochemical, and histopathological data for mechanisms identification and consistency with current adverse outcome pathways[J]. Int J Mol Sci,2024,25(10):5203.
[2]	Kolaric TO, Nincevic V, Kuna L, et al. Drug-induced fatty liver disease: pathogenesis and treatment[J]. J Clin Transl Hepatol,2021,9(5):731-737.
[3]	Xiang H, Wang W, Miao Z, et al. Evolving trends and drug class dynamics in drug-induced fatty liver disease over two decades[J]. Metab Target Organ Damage,2025,5:50. doi: 10.20517/mtod.2025.78
[4]	Lee B, Jung EA, Yoo JJ, et al. Prevalence, incidence and risk factors of tamoxifen-related non-alcoholic fatty liver disease: a systematic review and meta-analysis[J]. Liver Int,2020,40(6):1344-1355. doi: 10.1111/liv.14434
[5]	Kilani Y, Mosquera DAG, Fennell K, et al. Assessing the impact of metabolic syndrome on liver outcomes in methotrexate users: a retrospective cohort study[J]. J Clin Med,2025,14(19):6799.
[6]	López-Pascual E, Moreno-Torres M, Moro E, et al. Ontogeny of drug-induced fatty liver disease (DIFLD): from key initiating events to disease phenotypes[J]. Arch Toxicol,2025,99(12):5075-5091.
[7]	Borgne-Sanchez A, Fromenty B. Mitochondrial dysfunction in drug-induced hepatic steatosis: recent findings and current concept[J]. Clin Res Hepatol Gastroenterol,2025,49(3):102529.
[8]	Li G, Hu Y, Zhao H, et al. Slow metabolism-driven amplification of hepatic PPARγ agonism mediates benzbromarone-induced obesity-specific liver injury[J]. Adv Sci,2025,12(3):e2409126.
[9]	Begriche K, Penhoat C, Bernabeu-Gentey P, et al. Acetaminophen-induced hepatotoxicity in obesity and nonalcoholic fatty liver disease: a critical review[J]. Livers,2023,3(1):33-53.
[10]	Allard J, Le Guillou D, Begriche K, et al. Drug-induced liver injury in obesity and nonalcoholic fatty liver disease[J]. Adv Pharmacol,2019,85:75-107.
[11]	Kučera O, Roušar T, Staňková P, et al. Susceptibility of rat non-alcoholic fatty liver to the acute toxic effect of acetaminophen[J]. J Gastroenterol Hepatol,2012,27(2):323-330.
[12]	Li X, Wang L, Li D, et al. Dyslipidemia is a risk factor for the incidence and severity of drug-induced liver injury (DILI): a retrospective population-based study in China[J]. Med Sci Monit,2019,25:3344-3353.
[13]	Xiang Q, Wen J, Zhou Z, et al. Effect of hydroxy-α-sanshool on lipid metabolism in liver and hepatocytes based on AMPK signaling pathway[J]. Phytomedicine,2024,132:155849.
[14]	Verma BK, Bhalgama D, Thakur P, et al. Drug-induced liver injury: mitochondrial mechanisms, biomarkers, and emerging therapeutic strategies[J]. Chem Res Toxicol,2026,39(5):786-795.
[15]	Allard J, Bucher S, Massart J, et al. Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity[J]. Cell Biol Toxicol,2021,37(2):151-175.
[16]	Chen P, Yao L, Yuan M, et al. Mitochondrial dysfunction: a promising therapeutic target for liver diseases[J]. Genes Dis,2024,11(3):101115.
[17]	Begriche K, Massart J, Robin MA, et al. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver[J]. J Hepatol,2011,54(4):773-794.
[18]	Zhu CY, Yu PH, Sun Q, et al. Nuclear receptors in metabolism and diseases: mechanistic and therapeutic insights[J]. Pharmacol Res,2025,218:107862.
[19]	Norris JE, Berry-Kravis EM, Harnett MD, et al. Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile X syndrome[J]. Mol Autism,2024,15(1):47.
[20]	Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease[J]. J Hepatol,2015,62(3):720-733.
[21]	Okazaki H, Goldstein JL, Brown MS, et al. LXR-SREBP-1c-phospholipid transfer protein axis controls very low density lipoprotein (VLDL) particle size[J]. J Biol Chem,2010,285(9):6801-6810.
[22]	Zhang H, He C, Pu Z, et al. New insights into Lambda-cyhalothrin-induced lipid metabolism disorder in liver: crosstalk between oxidative stress and PPARα signaling pathway[J]. Chem Biol Interact,2026,424:111872.
[23]	Fougerat A, Bruse J, Polizzi A, et al. Lipid sensing by PPARα: role in controlling hepatocyte gene regulatory networks and the metabolic response to fasting[J]. Prog Lipid Res,2024,96:101303.
[24]	Wallstab C, Eleftheriadou D, Schulz T, et al. A unifying mathematical model of lipid droplet metabolism reveals key molecular players in the development of hepatic steatosis[J]. FEBS J,2017,284(19):3245-3261.
[25]	Mashek DG, Khan SA, Sathyanarayan A, et al. Hepatic lipid droplet biology: getting to the root of fatty liver[J]. Hepatology,2015,62(3):964-967.
[26]	Hooper AJ, Burnett JR, Watts GF. Contemporary aspects of the biology and therapeutic regulation of the microsomal triglyceride transfer protein[J]. Circ Res,2015,116(1):193-205.
[27]	Shin S, Kim J, Lee JY, et al. Mitochondrial quality control: its role in metabolic dysfunction-associated steatotic liver disease (MASLD)[J]. J Obes Metab Syndr,2023,32(4):289-302.
[28]	Cicuéndez B, Ruiz-Garrido I, Mora A, et al. Stress kinases in the development of liver steatosis and hepatocellular carcinoma[J]. Mol Metab,2021,50:101190.
[29]	Bathish B, Robertson H, Dillon JF, et al. Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2[J]. Free Radic Biol Med,2022,188:221-261.
[30]	Yu T, Luo L, Xue J, et al. Gut microbiota-NLRP3 inflammasome crosstalk in metabolic dysfunction-associated steatotic liver disease[J]. Clin Res Hepatol Gastroenterol,2024,48(8):102458.
[31]	Jiang X, Li Y, Fu D, et al. Caveolin-1 ameliorates acetaminophen-aggravated inflammatory damage and lipid deposition in non-alcoholic fatty liver disease via the ROS/TXNIP/NLRP3 pathway[J]. Int Immunopharmacol,2023,114:109558.
[32]	Zhao Y, Li JZ, Liu YG, et al. Clinical features and prognosis of drug-induced liver injury in patients with non-alcoholic fatty liver[J]. World J Hepatol,2025,17(2):101741.
[33]	Michaut A, Moreau C, Robin MA, et al. Acetaminophen-induced liver injury in obesity and nonalcoholic fatty liver disease[J]. Liver Int,2014,34(7):e171-e179.
[34]	Masubuchi Y, Miyauchi K. Metabolism-dependent inhibition of CYP2E1 by isoniazid, a mediator of idiosyncratic liver injury[J]. Chem Biol Interact,2024,400:111160.
[35]	Govaere O, Cockell SJ, Zatorska M, et al. Pharmacogene expression during progression of metabolic dysfunction-associated steatotic liver disease: studies on mRNA and protein levels and their relevance to drug treatment[J]. Biochem Pharmacol,2024,228:116249.
[36]	Pontikoglou CG, Filippatos TD, Matheakakis A, et al. Steatotic liver disease in the context of hematological malignancies and anti-neoplastic chemotherapy[J]. Metabolism,2024,160:156000.
[37]	Cataldi M, Manco F, Tarantino G. Steatosis, steatohepatitis and cancer immunotherapy: an intricate story[J]. Int J Mol Sci,2021,22(23):12947.