Targeting the ER stress sensor IRE1 protects the liver from fibrosis through the downregulation of the proteostasis factor P4HB/PDIA1

BACKGROUND AIMS: Collagen is the main cargo of the secretory pathway, contributing to hepatic fibrogenesis due to extensive accumulation of extracellular matrix. An excess of collagen deposition is a characteristic feature of several chronic liver diseases. Collagen overproduction imposes pressure on the secretory pathway, altering endoplasmic reticulum (ER) proteostasis. Here, we investigated the possible contribution of the unfolded protein response, the main adaptive pathway that monitors and adjusts protein production capacity at the ER, to collagen biogenesis and liver disease. APPROACH RESULTS: We used multi-mice models combined with multi-omics approaches followed by cell culture studies. In addition, we validated results using human metabolic dysfunction-associated steatohepatitis (MASH) samples. Genetic ablation of the ER stress sensor IRE1 in the liver using conditional knockout mice reduced liver damage and collagen deposition in models of fibrosis, steatosis, and acute hepatotoxicity. Proteomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1) as a major IRE1-regulated gene, a critical factor involved in collagen maturation. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER, reducing its secretion, and this phenotype is rescued by P4HB/PDIA1 overexpression. Analyses of human MASH samples revealed a positive correlation between IRE1 signaling and P4HB/PDIA1 expression as well as the severity of the disease. CONCLUSIONS: Altogether, our results establish a role of the IRE1/P4HB axis in the regulation of collagen production and support its implication in the pathogenesis of liver fibrosis.