酒精性肝病 (ALD) 包括从单纯性脂肪变性到肝硬化，甚至肝癌等各种病症。近年来，它受到了全球的广泛关注。尽管如此，针对 ALD 的有效药物治疗仍然难以捉摸，而且该疾病的核心机制尚未完全了解。 S100A16 是一种新发现的钙结合蛋白，与脂质代谢有关。我们的研究发现 ALD 患者的血清和肝组织中 S100A16 蛋白水平升高。在高酗酒小鼠模型中，肝脏 S100A16 表达也出现了类似的激增。 S100a16 敲低可减轻乙醇引起的肝损伤、脂肪变性和炎症。相反，S100a16转基因小鼠则表现出加重的现象。从机制上讲，我们将中脑星形胶质细胞源性神经营养因子（MANF）确定为 S100a16 缺失下游的受调控实体。 MANF 抑制酒精刺激诱导的 ER 应激信号转导。同时，MANF沉默抑制了S100a16敲除对乙醇诱导的原代肝细胞脂滴积累的抑制作用。我们的数据表明，S100a16 缺失可以保护小鼠免受酒精性肝脂质积累和炎症的影响，这依赖于上调 MANF 和抑制 ER 应激。这为 ALD 治疗提供了潜在的治疗途径。© 作者。

Alcoholic liver disease (ALD) encompasses conditions ranging from simple steatosis to cirrhosis and even liver cancer. It has gained significant global attention in recent years. Despite this, effective pharmacological treatments for ALD remain elusive, and the core mechanisms underlying the disease are not yet fully comprehended. S100A16, a newly identified calcium-binding protein, is linked to lipid metabolism. Our research has discovered elevated levels of the S100A16 protein in both serum and liver tissue of ALD patients. A similar surge in hepatic S100A16 expression was noted in a Gao-binge alcohol feeding mouse model. S100a16 knockdown alleviated ethanol-induced liver injury, steatosis and inflammation. Conversely, S100a16 transgenic mice showed aggravating phenomenon. Mechanistically, we identify mesencephalic astrocyte-derived neurotrophic factor (MANF) as a regulated entity downstream of S100a16 deletion. MANF inhibited ER-stress signal transduction induced by alcohol stimulation. Meanwhile, MANF silencing suppressed the inhibition effect of S100a16 knockout on ethanol-induced lipid droplets accumulation in primary hepatocytes. Our data suggested that S100a16 deletion protects mice against alcoholic liver lipid accumulation and inflammation dependent on upregulating MANF and inhibiting ER stress. This offers a potential therapeutic avenue for ALD treatment.© The author(s).