对乙酰氨基酚（APAP）肝损伤是常见的公共健康安全问题，氧化应激在其发病机制中起重要作用。缺氧诱导因子（HIFs）是一组缺氧及氧化应激调控因子。有研究表明HIF-1促进APAP肝损伤，但机制不明。我们在预实验中发现APAP诱导肝组织HIF-1/2水平升高，敲除之则明显提高肝组织PPARα/FGF21/Nrf2的表达水平并减轻APAP肝损伤。我们推测HIFs是PPARα的负性调控因子，通过抑制肝细胞PPARα的表达水平而影响PPARα/FGF21/Nrf2抗氧化通路，从而阻碍肝组织内源性抗氧化保护系统发挥功能。我们设想通过一系列转录因子研究和siRNA干扰实验在肝细胞水平明确HIFs对PPARα的转录调控关系及其对抗氧化通路的影响。采用HIFs/PPARα双敲除小鼠在活体水平进一步阐明该调控关系的功能后果。本研究将可能揭示HIFs调节肝细胞氧化应激的新机制，并为APAP肝损伤提供新治疗策略。

Acetaminophen (APAP) hepatotoxicity is one of the leading causes of acute liver failure, and also a serious medical problem for public health. Some severe cases even require liver transplantation. Oxidative stress plays a critical role in the pathogenesis of APAP-induced hepatotoxicity. Hypoxia-inducible factors (HIFs) are critical transcription factors that control oxygen homeostasis and oxidative stress. HIFs have reportedly been implicated in the pathogenesis of APAP-induced liver injury, but the mechanism is unknown. Our preliminary experiment found APAP could induce hepatic HIF1 and HIF2 stabilization. Hepatocyte-specific knockout of HIF1 and HIF2 could significantly reduce APAP-induced oxidative stress and liver injury. Moreover, HIF-knockout up-regulated the levels of PPARα/FGF21/Nrf2 in liver tissues. Based on these findings, we hypothesize that HIFs are key suppressors of PPARα in the liver, thereby compromising the adaptive defense mechanisms against oxidative stress via inhibiting PPARα/FGF21/Nrf2 antioxidant pathway. To prove this theory, we plan to employ chromatin precipitation, gel electrophoresis migration experiment(EMSA) and luciferase report assay to explorer the regulatory relationship between HIFs and PPARα in hepatocytes. In vivo studies will also be carried out in HIF-1β/PPARα double knockout mice. Further, siRNA interference will be used to study the antioxidant effect of PPARα/FGF21/Nrf2 pathway in hepatocytes. These studies may help to facilitate understanding of the role of HIF in oxidative stress and APAP injury, which may serve as a novel therapeutic target.