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Abstract：
Drug induced fatty liver disease (DIFLD) is a form of drug-induced liver injury (DILI), which can also be included in the more general metabolic dysfunction-associated steatotic liver disease (MASLD), which specifically refers to the accumulation of fat in the liver unrelated to alcohol intake. A bi-directional relationship between DILI and MASLD is likely to exist: while certain drugs can cause MASLD by acting as pro-steatogenic factors, MASLD may make hepatocytes more vulnerable to drugs. Having a pre-existing MASLD significantly heightens the likelihood of experiencing DILI from certain medications. Thus, the prevalence of steatosis within DILI may be biased by pre-existing MASLD, and it can be concluded that the genuine true incidence of DIFLD in the general population remains unknown. In certain individuals, drug-induced steatosis is often accompanied by concomitant injury mechanisms such as oxidative stress, cell death, and inflammation, which leads to the development of drug-induced steatohepatitis (DISH). DISH is much more severe from the clinical point of view, has worse prognosis and outcome, and resembles MASH (metabolic-associated steatohepatitis), as it is associated with inflammation and sometimes with fibrosis. A literature review of clinical case reports allowed us to examine and evaluate the clinical features of DIFLD and their association with specific drugs, enabling us to propose a classification of DIFLD drugs based on clinical outcomes and pathological severity: Group 1, drugs with low intrinsic toxicity (e.g., ibuprofen, naproxen, acetaminophen, irinotecan, methotrexate, and tamoxifen), but expected to promote/aggravate steatosis in patients with pre-existing MASLD; Group 2, drugs associated with steatosis and only occasionally with steatohepatitis (e.g., amiodarone, valproic acid, and tetracycline); and Group 3, drugs with a great tendency to transit to steatohepatitis and further to fibrosis. Different mechanisms may be in play when identifying drug mode of action: (1) inhibition of mitochondrial fatty acid β-oxidation; (2) inhibition of fatty acid transport across mitochondrial membranes; (3) increased de novo lipid synthesis; (4) reduction in lipid export by the inhibition of microsomal triglyceride transfer protein; (5) induction of mitochondrial permeability transition pore opening; (6) dissipation of the mitochondrial transmembrane potential; (7) impairment of the mitochondrial respiratory chain/oxidative phosphorylation; (8) mitochondrial DNA damage, degradation and depletion; and (9) nuclear receptors (NRs)/transcriptomic alterations. Currently, the majority of, if not all, adverse outcome pathways (AOPs) for steatosis in AOP-Wiki highlight the interaction with NRs or transcription factors as the key molecular initiating event (MIE). This perspective suggests that chemical-induced steatosis typically results from the interplay between a chemical and a NR or transcription factors, implying that this interaction represents the primary and pivotal MIE. However, upon conducting this exhaustive literature review, it became evident that the current AOPs tend to overly emphasize this interaction as the sole MIE. Some studies indeed support the involvement of NRs in steatosis, but others demonstrate that such NR interactions alone do not necessarily lead to steatosis. This view, ignoring other mitochondrial-related injury mechanisms, falls short in encapsulating the intricate biological mechanisms involved in chemically induced liver steatosis, necessitating their consideration as part of the AOP\'s map road as well.
摘要：
药物性脂肪肝（DIFLD）是药物性肝损伤（DILI）的一种形式，它也可以包括在更一般的代谢功能障碍相关的脂肪变性肝病（MASLD）中，具体是指与酒精摄入无关的脂肪在肝脏中的积累。DILI和MASLD之间可能存在双向关系：虽然某些药物可以通过充当促脂肪因子而引起MASLD，MASLD可能使肝细胞更容易受到药物的影响。具有预先存在的MASLD显着增加了从某些药物经历DILI的可能性。因此，DILI内脂肪变性的患病率可能因预先存在的MASLD而有偏差，可以得出结论，DIFLD在普通人群中的真正真实发生率仍然未知。在某些个人中，药物诱导的脂肪变性通常伴有伴随的损伤机制，如氧化应激，细胞死亡,和炎症，这导致药物诱导的脂肪性肝炎（DISH）的发展。从临床角度来看，DISH要严重得多，预后和结果较差，类似于MASH（代谢相关脂肪性肝炎），因为它与炎症有关，有时与纤维化有关。临床病例报告的文献综述使我们能够检查和评估DIFLD的临床特征及其与特定药物的关联，使我们能够根据临床结果和病理严重程度对DIFLD药物进行分类：第1组，具有低内在毒性的药物(例如，布洛芬,萘普生,对乙酰氨基酚,伊立替康,甲氨蝶呤,和他莫昔芬)，但预期会促进/加重预先存在的MASLD患者的脂肪变性；第2组，与脂肪变性相关的药物，仅偶尔与脂肪性肝炎（例如，胺碘酮,丙戊酸,和四环素）；和第3组，具有向脂肪性肝炎和进一步纤维化转移的趋势的药物。确定药物作用模式时可能会发挥不同的机制：（1）抑制线粒体脂肪酸β-氧化；（2）抑制脂肪酸跨线粒体膜运输；（3）从头脂质合成增加；（4）通过抑制微粒体甘油三酯转移蛋白减少脂质输出；（5）诱导线粒体通透性转换孔开放；（6）线粒体跨膜电位的消散；（7）呼吸链/线粒体DNA氧化损伤的线粒体磷酸化（8）降解和耗尽;和(9)核受体(NRs)/转录组改变。目前,大多数,如果不是全部,AOP-Wiki中脂肪变性的不良结局通路(AOP)强调了与NRs或转录因子的相互作用是关键的分子启动事件(MIE).这种观点表明，化学诱导的脂肪变性通常是由化学物质和NR或转录因子之间的相互作用引起的。这意味着这种相互作用代表了主要和关键的MIE。然而,在进行这篇详尽的文献综述后，很明显，当前的AOPs倾向于过分强调这种相互作用是唯一的MIE。一些研究确实支持NRs参与脂肪变性，但其他人证明，单独的NR相互作用并不一定导致脂肪变性。这个观点,忽略其他线粒体相关的损伤机制，在封装涉及化学诱导的肝脏脂肪变性的复杂的生物学机制，也有必要将它们作为AOP地图道路的一部分。
