Hepatocyte-intrinsic ER stress and NRF2 initiate primary sclerosing cholangitis, providing therapeutic insights.
Tao Lianyuan, He Peng, Ge Jiachen, Guan Qifei, Wang Erpei, Mohanty Ipsita, Bez Cristina, Song Won-Suk, Lan Ling, Qi Jingjing, Zhang Yueqi, Zhang Peng, Liu Yuxiao, Mukkala Avinash, Feng Yechen, Zhu Mandy, Zhou Qiong, Ai Tingting, Watari Kosuke, Antonucci Laura, Gu Li, Huang Li, Qin Tao, Li Deyu, Xiu Dianrong, Jang Cholsoon, Varner Judith A, Dorrestein Pieter C, Sun Beicheng, Karin Michael
Abstract
primary sclerosing cholangitis (PSC) is a severe liver disease that can progress to cholangiocarcinoma. Therapeutic development has been hindered by the rarity of PSC and by its poorly understood origin, which reflects incompletely defined genetic and environmental risk factors. Here we describe a mouse model that combines two suspected environmental risk factors, hepatocyte-intrinsic ER stress and oxidative stress, which leads to activation of transcription factor NRF2 in both hepatocytes and cholangiocytes. Genetically affected mice, as well as mice treated with an ER stress inducer and an NRF2 activator, progressed to PSC with human-like features. Specifically, hepatocyte-intrinsic ER stress in cooperation with activated NRF2 leads to indirect activation of JNK-JUN signaling, which abrogates HNF1α-stimulated Fxr gene transcription and reduces expression of the bile salt export pump BSEP. These signaling abnormalities, whose clinical relevance is supported by single cell transcriptomics of human PSC tissue, cause cholestasis, hepatocyte and bile canaliculi injury, biliary hyperplasia, and periductular fibrosis, which define PSC. Congruently, alleviation of cholestasis and/or inhibition of biliary hyperplasia resolve PSC in mice.
Key Findings
- Hepatocyte-intrinsic ER stress combined with oxidative stress activates NRF2 in hepatocytes and cholangiocytes, leading to primary sclerosing cholangitis (PSC) in a mouse model.
- Activation of NRF2 and ER stress induces JNK-JUN signaling, which suppresses HNF1α-driven Fxr gene transcription and reduces bile salt export pump (BSEP) expression, causing cholestasis and liver injury.
- Therapeutic interventions that alleviate cholestasis or inhibit biliary hyperplasia can resolve PSC in mice, highlighting potential treatment strategies.
Clinical Significance
This study elucidates the molecular mechanisms linking ER stress and NRF2 activation to PSC pathogenesis, providing new therapeutic targets to treat or prevent this severe liver disease.
Citation
Tao Lianyuan, He Peng, Ge Jiachenet al.. Hepatocyte-intrinsic ER stress and NRF2 initiate primary sclerosing cholangitis, providing therapeutic insights. Proceedings of the National Academy of Sciences of the United States of America. 2026-Aug-18.