PDIA6 as a novel pharmacological target for metabolic dysfunction-associated steatohepatitis via alleviating endoplasmic reticulum stress.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by hepatocyte ballooning, inflammation, and varying degrees of fibrosis. Protocatechuic acid (PCA), a naturally occurring phenolic compound found in many fruits and vegetables, exhibits various pharmacological properties. However, the precise mechanisms and molecular targets for MASH treatment remain unclear. In this study, we demonstrate that PCA ameliorates hepatic steatosis, fibrosis, and inflammation in MCD-fed mice and reduces lipid accumulation in hepatocytes via the IRE1-XBP1s signaling pathway. By using activity-based protein profiling (ABPP), we revealed that PCA binds protein disulfide isomerase A6 (PDIA6). Co-immunoprecipitation mass spectrometry (Co-IP-MS) analysis demonstrates that PCA enhances the interaction between PDIA6 and IRE1. This interaction suppresses the IRE1-XBP1s signaling pathway, reduces endoplasmic reticulum stress, and contributes to an anti-lipid deposition effect. PDIA6 knockdown inhibits lipid accumulation and eliminates the therapeutic impact of PCA. Collectively, these findings identify PDIA6 as a novel pharmacological target for PCA in the treatment of MCD-induced MASH, while advancing our understanding of disease pathogenesis.