Conjugated bile acids facilitate cholangiocyte senescence to promote cholestatic liver diseases via STING signaling

Guifang Fan; Xin Li; Yiran Li; Shuni Duan; Wenqing Qin; Yajing Li; Rong Sun; Kaihong Xie; Zixuan Huo; Jiaorong Qu; Runping Liu

doi:10.1016/j.jare.2026.03.020

Conjugated bile acids facilitate cholangiocyte senescence to promote cholestatic liver diseases via STING signaling

J Adv Res. 2026 Mar 12:S2090-1232(26)00239-0. doi: 10.1016/j.jare.2026.03.020. Online ahead of print.

Authors

Guifang Fan¹, Xin Li¹, Yiran Li², Shuni Duan¹, Wenqing Qin¹, Yajing Li³, Rong Sun⁴, Kaihong Xie³, Zixuan Huo³, Jiaorong Qu³, Runping Liu⁵

Affiliations

¹ School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China.
² Bioinformatics facility, National Infrastructure for Translational Medicine, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Beijing 100730, China.
³ School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China.
⁴ The Second Hospital of Shandong University, Shan Dong University, 247 Bei Yuan Da Jie, Jinan 250033, China.
⁵ School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China. Electronic address: liurunping@bucm.edu.cn.

PMID: 41831676
DOI: 10.1016/j.jare.2026.03.020

Abstract

Introduction: Cholestatic liver disease can progress to advanced stages if left untreated and is lack of effective therapeutic options, highlighting the urgent need for new therapeutic targets.

Objectives: We aim to investigate the involvement of conjugated bile acids and STING signaling in the progression of cholestatic liver diseases.

Methods: We studied cholestatic liver injury in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), as well as in Abcb4^-/- mice and in mice subjected to bile duct ligation (BDL). Single-cell RNA sequencing (scRNA-seq) of clinical samples, bulk RNA sequencing (RNA-seq) of isolated primary hepatic cells, and abundant biochemical analysis were analyzed to reveal the damage-response pattern during cholestasis.

Results: We found that STING activation was correlated with the severity of liver injuries in patients with PBC and PSC, as well as in BDL and Abcb4^-/- mice. Tmem173^-/- mice exhibited significant protection against cholestasis-induced ductular reaction, inflammation, and fibrosis. Mechanistically, our results uncovered the cellular heterogeneity of the damage-response pattern during cholestasis. In cholangiocytes, substantial accumulation of conjugated primary bile acids significantly induced mitochondrial damage through the opening of the mitochondrial permeability transition pore, resulting in the production and leakage of oxidized DNA, which facilitates the establishment of senescence-associated secretory phenotype (SASP) by activating STING. The chemoattractive SASP of cholangiocytes then promoted the infiltration and activation of macrophages. Additionally, damage-associated molecular patterns derived from cholangiocytes further triggered the activation of inflammasome and non-lethal pyroptosis in macrophages, which were abrogated by pharmacological or genetic blockade of STING.

Conclusion: The present study delineates a novel intrahepatic damage-response map during cholestasis and underscores STING signaling as a promising therapeutic target for cholangiopathies.

Keywords: Cholangiocyte senescence; Cholangiopathies; Conjugated bile acid; Inflammasome activation; STING.