2. Academic Validation
  3. The secretory protein, CLCF1, improves cholestatic liver disease by inhibiting hepatic bile acid synthesis and promoting bile acid excretion

The secretory protein, CLCF1, improves cholestatic liver disease by inhibiting hepatic bile acid synthesis and promoting bile acid excretion

  • Commun Biol. 2026 Mar 16;9(1):370. doi: 10.1038/s42003-026-09847-w.
Man Liu # 1 2,  Yingxi Su # 1,  Yujie Hu # 1,  Meng Shen 1,  Suriguge Bao 1 3,  Yanqing Gong 1 4,  Yinglan Ji 1 4,  Lingfei Wang 1,  Yujie Zhang 5,  Xiaoyi Wang 6,  Hui Yang 1,  Yongsheng Chang 7 8,  Lu Zhou 9
Affiliations

Affiliations

  • 1 Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China.
  • 2 Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.
  • 3 Department of Gastroenterology, The Second Affiliated Hospital of Baotou Medical College, Baotou, China.
  • 4 Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, China.
  • 5 Department of Pathology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.
  • 6 Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin, China.
  • 7 Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China. [email protected].
  • 8 Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China. [email protected].
  • 9 Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China. [email protected].
  • # Contributed equally.
PMID: 41840139 DOI: 10.1038/s42003-026-09847-w
Abstract

Cholestatic liver disease (CLD) is characterized by disrupted bile acid (BA) homeostasis and excessive accumulation of toxic bile acids in the liver. While both genetic and acquired factors are known to contribute to its pathogenesis, the full spectrum of underlying pathological mechanisms remains incompletely understood, and treatment options are limited. Cardiotrophin-like cytokine factor 1 (CLCF1), a CNTFR ligand, plays a pivotal role in energy metabolic homeostasis, yet its role in cholestasis remains unclear. Here, we show that hepatic CLCF1 expression is markedly upregulated in cholestatic patients and mouse models (all mice used in this study were male). Hepatocyte-specific Cntfr deletion exacerbates DDC-induced cholestasis and fibrosis, whereas AAV-mediated hepatic Clcf1 overexpression attenuates cholestatic liver injury and fibrosis in both Abcb4 knockout (Mdr2-/-) and DDC-fed mice. Mechanistically, CLCF1 suppresses BA synthesis Enzymes independently of hepatic FXR-SHP signaling, and selectively enriches FXR-agonistic BAs (e.g., LCA) in the gut, activating the intestinal FXR-FGF15 axis. Gut-restricted FXR antagonism partially reverses CLCF1-mediated hepatoprotection, underscoring the gut-liver axis as a critical effector. Furthermore, CLCF1 remodels the microbiota to favor Firmicutes, enhancing BA excretion. Altogether, our data demonstrate that CLCF1 mitigates CLD through suppressing BA synthesis and enhancing BA excretion. CLCF1 may represent a promising therapeutic avenue for cholestasis.

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