Acetaminophen (APAP) toxicity is the leading cause of drug-induced liver failure, which is closely related to mitochondrial dysfunction and oxidative damage. Studies in clinical trials and in animal models have shown that omega-3 polyunsaturated fatty acids (n-3 PUFAs) affect the progression of various types of liver damage. Interestingly, the sex-dependent effect of n-3 PUFAs on human health has also been well documented. However, it is unknown whether supplementation of n-3 PUFAs modulates the pathogenesis of APAP-induced liver failure with sex-specificity. Our results showed that both endogenous and exogenous n-3 PUFAs significantly aggravated the APAP-induced liver injury in male mice, whereas the opposite effects were observed in females. In vivo and in vitro studies demonstrated that estrogen contributes to the gender difference in the regulation of n-3 PUFAs on APAP overdose. We found that n-3 PUFA-mediated regulation of hepatic oxidative stress response and autophagy upon APAP challenge is distinct between male and female mice. Moreover, we provided evidence that β-catenin signaling activation is responsible for the sex-dependent regulation of APAP hepatotoxicity by n-3 PUFAs. Together, these findings indicated that supplementation with n-3 PUFAs displays sex-differential effect on APAP hepatotoxicity and could have profound significance in the clinical management for drug-induced liver injury.

中文翻译：

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性别差异对Omega-3多不饱和脂肪酸对乙酰氨基酚引起的急性肝衰竭的影响。

对乙酰氨基酚（APAP）毒性是药物性肝衰竭的主要原因，其与线粒体功能障碍和氧化损伤密切相关。在临床试验和动物模型中的研究表明，ω-3多不饱和脂肪酸（n-3 PUFA）影响各种类型的肝损伤的进展。有趣的是，n-3 PUFA对人类健康的性别依赖性效应也已得到充分证明。然而，尚不清楚补充n-3 PUFA是否以性别特异性调节APAP诱导的肝衰竭的发病机理。我们的研究结果表明，内源性和外源性n-3 PUFA均可显着加剧雄性小鼠APAP诱导的肝损伤，而雌性小鼠则观察到相反的作用。体内和体外研究表明，雌激素可导致AP-3过量时n-3 PUFA的调节中的性别差异。我们发现，n-3 PUFA介导的对APAP攻击的肝氧化应激反应和自噬的调节在雄性和雌性小鼠之间是不同的。此外，我们提供的证据表明β -catenin信号激活负责n-3 PUFA对APAP肝毒性的性别依赖性调节。总之，这些发现表明，n-3 PUFA的补充对APAP的肝毒性具有性别差异，并且在药物性肝损伤的临床管理中可能具有深远的意义。