Abstract：
The incidence of nonalcoholic steatohepatitis (NASH) is related with perfluorooctane sulfonate (PFOS), yet the mechanism remains ill-defined. Mounting evidence suggests that ferroptosis plays a crucial role in the initiation of NASH. In this study, we used mice and human hepatocytes L-02 to investigate the role of ferroptosis in PFOS-induced NASH and the effect and molecular mechanism of PFOS on liver ferroptosis. We found here that PFOS caused NASH in mice, and lipid accumulation and inflammatory response in the L-02 cells. PFOS induced hepatic ferroptosis in vivo and in vitro, as evidenced by the decrease in glutathione peroxidase 4 (GPX4), and the increases in cytosolic iron, acyl-CoA synthetase long-chain family member 4 (ACSL4) and lipid peroxidation. In the PFOS-treated cells, the increases in the inflammatory factors and lipid contents were reversed by ferroptosis inhibitor. PFOS-induced ferroptosis was relieved by autophagy inhibitor. The expression of mitochondrial calcium uniporter (MCU) was accelerated by PFOS, leading to subsequent mitochondrial calcium accumulation, and inhibiting autophagy reversed the increase in MCU. Inhibiting mitochondrial calcium reversed the variations in GPX4 and cytosolic iron, without influencing the change in ACSL4, induced by PFOS. MCU interacted with ACSL4 and the siRNA against MCU reversed the changes in ACSL4，GPX4 and cytosolic iron systemically. This study put forward the involvement of hepatic ferroptosis in PFOS-induced NASH and identified MCU as the mediator of the autophagy-dependent ferroptosis.
摘要：
非酒精性脂肪性肝炎（NASH）的发病率与全氟辛烷磺酸（PFOS）有关，然而，机制仍然不明确。越来越多的证据表明，铁性凋亡在NASH的启动中起着至关重要的作用。在这项研究中,我们使用小鼠和人肝细胞L-02研究了铁凋亡在PFOS诱导的NASH中的作用以及PFOS对肝脏铁凋亡的影响和分子机制。我们在这里发现全氟辛烷磺酸在小鼠中引起NASH，以及L-02细胞中的脂质积累和炎症反应。全氟辛烷磺酸在体内和体外诱导肝脏铁凋亡，正如谷胱甘肽过氧化物酶4（GPX4）的减少所证明的那样，和胞质铁的增加，酰基辅酶A合成酶长链家族成员4（ACSL4）和脂质过氧化。在全氟辛烷磺酸处理的细胞中，铁凋亡抑制剂逆转了炎症因子和脂质含量的增加。自噬抑制剂减轻了PFOS诱导的铁凋亡。PFOS促进线粒体钙离子(MCU)的表达,导致随后的线粒体钙积累，抑制自噬逆转了MCU的增加。抑制线粒体钙逆转了GPX4和胞质铁的变化，不影响PFOS诱导的ACSL4的变化。MCU与ACSL4相互作用，针对MCU的siRNA系统逆转了ACSL4、GPX4和胞质铁的变化。本研究提出了肝脏铁凋亡参与PFOS诱导的NASH，并确定MCU是自噬依赖性铁凋亡的介质。
