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Deoxycholic Acid Promotes Pyroptosis in Free Fatty Acid-Induced Steatotic Hepatocytes by Inhibiting PINK1-Mediated Mitophagy

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Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), which can lead to liver fibrosis and cirrhosis. Bile acid levels are correlated with markers of hepatic injury in NASH, suggesting a possible role for bile acids in the progression of NAFLD. Here, we examined the role of deoxycholic acid (DCA) in driving steatotic hepatocytes to pyroptosis, a pro-inflammatory form of programmed cell death. HepG2 cells were stimulated with odium oleate and sodium palmitate for modeling steatotic hepatocytes and then treated with DCA alone or in combination with a specific mitophagy agonist, carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Our results showed that DCA dose-dependently induced a pro-inflammatory response in steatotic hepatocytes but had no significant effect on lipid accumulation. Moreover, activation of the NLRP3 inflammasome and pyroptosis were triggered by DCA. Expression levels of the mitophagy markers PTEN-induced kinase 1 (PINK1) and E3 ubiquitin ligase Parkin were significantly diminished by DCA, whereas induction of mitophagy by CCCP prevented DCA-induced inflammatory response and restored the pyroptosis. Collectively, our data showed that DCA-induced pyroptosis involves the inhibition of PINK1-mediated mitophagy and the activation of the NLRP3 inflammasome. These findings provide insight into the association of DCA with mitophagy, pyroptosis, and inflammation in NASH.

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Discipline construction project of Guangdong Medical University (4SG21016G); Funds for PHD researchers of Guangdong Medical University in 2019 (B2019001).

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Xuebin Gao and Honghui Guo designed the study. Xuebin Gao, Xuan Zhu, Yan Xin, Xiaozhuan Lin, Xiang Li, and Meiqing Mai performed the experiments and analyzed the data. Xuebin Gao and Yongdui Ruan wrote the manuscript. Honghui Guo revised the manuscript.

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Correspondence to Honghui Guo.

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Gao, X., Ruan, Y., Zhu, X. et al. Deoxycholic Acid Promotes Pyroptosis in Free Fatty Acid-Induced Steatotic Hepatocytes by Inhibiting PINK1-Mediated Mitophagy. Inflammation 45, 639–650 (2022).

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