Hepatocyte intrinsic ER stress and persistent NRF2 activation initiate primary sclerosing cholangitis, providing new therapeutic insights

To investigate the mechanisms by which hepatocyte-intrinsic stress responses contribute to PSC development, we performed single-nucleus RNA sequencing (snRNA-seq) on liver tissues from mouse models with endoplasmic reticulum (ER) stress and persistent NRF2 activation, along with control mice. These mice developed PSC-like pathology, including cholestasis, bile duct proliferation, inflammation, and fibrosis.

Transcriptomic analyses revealed activation of ER stress, NRF2, EGFR signaling pathway, and JNK signaling pathways, along with suppression of the FXR–BSEP axis and disrupted bile acid metabolism. Notably, hepatocyte-intrinsic stress responses were associated with disease initiation, whereas NRF2 activation in cholangiocytes contributed to biliary proliferation and disease progression. Cross-species integration with human PSC datasets confirmed similar transcriptional alterations.