Hepatocyte senescence is a key event participating in the progression of alcoholic liver disease. Autophagy is a critical biological process that controls cell fates by affecting cell behaviors like senescence. Pterostilbene is a natural compound with hepatoprotective potential; however, its implication for alcoholic liver disease was not understood. This study was aimed to investigate the therapeutic effect of pterostilbene on alcoholic liver disease and elucidate the potential mechanism. Our results showed that pterostilbene alleviated ethanol-triggered hepatocyte damage and senescence. Intriguingly, pterostilbene decreased the protein abundance of cellular communication network factor 1 (CCN1) in ethanol-exposed hepatocytes, which was essential for pterostilbene to execute its anti-senescent function. In vivo studies verified the anti-senescent effect of pterostilbene on hepatocytes of alcohol-intoxicated mice. Pterostilbene also relieved senescence-associated secretory phenotype (SASP), redox imbalance, and steatosis by suppressing hepatic CCN1 expression. Mechanistically, pterostilbene-forced CCN1 reduction was dependent on posttranscriptional regulation via autophagy machinery but not transcriptional regulation. To be specific, pterostilbene restored autophagic flux in damaged hepatocytes and activated p62-mediated selective autophagy to recognize and lead CCN1 to autolysosomes for degradation. The protein abundance of Sestrin2 (SESN2), a core upstream modulator of autophagy pathway, was decreased in ethanol-administrated hepatocytes but rescued by co-treatment with pterostilbene. Induction of SESN2 protein by pterostilbene rescued ethanol-triggered autophagic dysfunction in hepatocytes, which then reduced senescence-associated markers, postponed hepatocyte senescence, and relieved alcohol-caused liver injury and inflammation. In conclusion, this work discovered a novel compound pterostilbene with therapeutic implications for alcoholic liver disease and uncover its underlying mechanism.

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中文翻译：

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紫檀芪诱导 Sestrin2 通过 p62 依赖性选择性自噬降解 CCN1，从而抑制乙醇引发的肝细胞衰老

肝细胞衰老是参与酒精性肝病进展的关键事件。自噬是一个重要的生物过程，通过影响衰老等细胞行为来控制细胞命运。紫檀芪是一种具有保肝潜力的天然化合物；然而，其对酒精性肝病的影响尚不清楚。本研究旨在探讨紫檀芪对酒精性肝病的治疗作用并阐明其潜在机制。我们的结果表明紫檀芪减轻了乙醇引发的肝细胞损伤和衰老。有趣的是，紫檀芪降低了乙醇暴露的肝细胞中细胞通讯网络因子 1 (CCN1) 的蛋白质丰度，这对于紫檀芪执行其抗衰老功能至关重要。体内研究证实了紫檀芪对酒精中毒小鼠肝细胞的抗衰老作用。紫檀芪还通过抑制肝脏 CCN1 表达来缓解衰老相关的分泌表型 (SASP)、氧化还原失衡和脂肪变性。从机制上讲，紫檀芪迫使 CCN1 减少依赖于自噬机制的转录后调节，而不是转录调节。具体来说，紫檀芪可以恢复受损肝细胞中的自噬流，并激活p62介导的选择性自噬，识别并引导CCN1至自溶酶体降解。Sestrin2 (SESN2)（自噬途径的核心上游调节剂）的蛋白质丰度在乙醇施用的肝细胞中降低，但通过与紫檀芪共同处理而得以恢复。紫檀芪诱导SESN2蛋白可挽救乙醇引发的肝细胞自噬功能障碍，从而减少衰老相关标志物，推迟肝细胞衰老，缓解酒精引起的肝损伤和炎症。总之，这项工作发现了一种新型化合物紫檀芪，对酒精性肝病具有治疗意义，并揭示了其潜在机制。

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