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Senkyunolide A ameliorates cholestatic liver fibrosis by controlling CLCC1-mediated endoplasmic reticulum Ca2+ release

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Cholestatic liver disease is characterized by highly accumulated bile acids and cholangiocyte proliferation, resulting in the development of fibrosis, cirrhosis, and ultimately liver failure necessitating liver transplantation. Calcium (Ca2+) signaling is commonly dysregulated in cholestasis and serves as an important regulator mediating cell proliferation. However, the role of Ca2+-mediated cholangiocyte proliferation and treatment strategies in bile duct ligation (BDL)-induced liver injury remains poorly understood. By integrating transcriptomic analysis with molecular biology techniques, we explored the mechanisms of liver injury across BDL animal models, primary cholangiocytes, and human intrahepatic biliary epithelial cholangiocytes. Here, we found that a natural ingredient, senkyunolide A (SenA), effectively alleviated cholestasis-induced Ca2+ release from ER by inhibiting RYR channel, thereby preventing FIP200-mediated ER autophagy in response to Ca2+ transients on the cytosolic ER surface. Increased cytosolic Ca2+ further triggered ER stress, cholangiocyte cycle progression, and ductular reaction (DR). Importantly, SenA reversed the above process through its binding to chloride Channel CLIC Like 1 (CLCC1) for ubiquitination, thereby inhibiting CLCC1 activity and ER Ca2+ release. si-CLCC1-loaded liposomes targeting cholangiocytes enhanced the anti-DR effects of SenA. Collectively, by controlling ER release of Ca2+ in cholangiocytes, SenA presents potential for the development of therapeutic strategies aimed at addressing cholestatic fibrosis.

SenA inhibited Ca2+-mediated cholangiocyte proliferation by binding to and promoting the ubiquitination of CLCC1, thereby alleviating cholestatic liver fibrosis.

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Fig. 1: SenA ameliorated BDL-induced cholestatic liver fibrosis.
Fig. 2: SenA inhibited cholangiocyte proliferation in BDL mice.
Fig. 3: SenA inhibited cholangiocyte proliferation through the regulation of Ca2+ release from the ER.
Fig. 4: SenA suppressed the RYR-mediated release of Ca2+ from the ER.
Fig. 5: SenA reduced the release of Ca2+ from ER by ubiquitylating CLCC1.
Fig. 6: SenA inhibited the formation of FIP200 autophagy vesicles induced by increased Ca2+.
Fig. 7: SenA prevented the increase of intracellular Ca2+ and cell through the suppression of FIP200 autophagy vesicle formation.
Fig. 8: SenA ameliorated BDL-induced cholestatic liver damage by inhibiting CLCC1.

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Acknowledgements

This work was supported by grants from the Scientific Research Innovation Capability Support Project for Young Faculty (ZYGXQNJSKYCXNLZCXM-H4); National Natural Science Foundation of China (Grant No. 82322075 to RPL and 82274186 to XJYL); National High-Level Talents Special Support Program to XJYL; Beijing Municipal Science & Technology Commission (Grant No. 7212174 to XJYL); National Key Research and Development Program on Modernization of Traditional Chinese Medicine to XJYL; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (Grant No. ZYYCXTD-C-202006 to XJYL).

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  1. These authors contributed equally: Ya-jing Li, Meng-yu Guo.

Authors and Affiliations

  1. School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China

    Ya-jing Li, Meng-yu Guo, Jia-nan Li, Fu-kun Zhang, Xiao-yong Xue, Jiao-rong Qu, Lei Wang & Xiao-jiao-yang Li

  2. Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Ya-jing Li

  3. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China

    Wen-qing Qin, Yu-fei Li, Shuo Li & Run-ping Liu

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Contributions

YJL: methodology, formal analysis, writing—original draft. MYG: methodology, writing—original draft. WQQ: validation. JNL: methodology. YFL: validation. FKZ: methodology. XYX: methodology. RPL: investigation. SL: methodology. JRQ: investigation. LW: methodology. XJYL: conceptualization, writing—review and editing.

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Correspondence to Xiao-jiao-yang Li.

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Li, Yj., Guo, My., Qin, Wq. et al. Senkyunolide A ameliorates cholestatic liver fibrosis by controlling CLCC1-mediated endoplasmic reticulum Ca2+ release. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01615-6

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