Cepharanthine relieves nonalcoholic steatohepatitis through inhibiting STAT1/CXCL10 axis-mediated lipogenesis and inflammatory responses

  • J Ethnopharmacol. 2025 Feb 11:341:119358. doi: 10.1016/j.jep.2025.119358.
Pan Li  1 ,  Ruoyu Zhang  2 ,  Pingping Hu  3 ,  Tingting Wang  4 ,  Jianwei Wang  5
Affiliations
  • 1. College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Medical University, Chongqing, 400016, PR China. Electronic address: [email protected].
  • 2. School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, 999077, PR China.
  • 3. College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Medical University, Chongqing, 400016, PR China.
  • 4. College of Pharmacy, Chongqing Medical University, Chongqing, 400016, PR China; Chongqing Key Laboratory for Pharmaceutical Metabolism Research, Chongqing Medical University, Chongqing, 400016, PR China. Electronic address: [email protected].
  • 5. Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing Medical University, Chongqing, 400016, PR China. Electronic address: [email protected].
PMID: 39805479 DOI: 10.1016/j.jep.2025.119358
Abstract

Ethnopharmacological relevance: Stephania rotunda Lour., a medicinal herb, has been utilized in both Traditional Chinese Medicine (TCM) and Traditional Indian Medicine to treat conditions such as fever, dysentery, and inflammation. Cepharanthine (CEP), a primary active ingredient of Stephania rotunda Lour., has demonstrated a range of pharmacological activities, including anti-oxidative, anti-inflammatory, anti-cancer, anti-viral and Anti-parasitic properties. However, the effects and underlying mechanisms of CEP on improving nonalcoholic steatohepatitis (NASH) remain unclear.

Aim of the study: This study aimed to investigate the effects of CEP on mitigating diet-induced NASH and explore its underlying mechanisms.

Materials and methods: A High-Fat Diet (HFD) and the high levels of free fatty acids (FFA) were used to establish in vivo and in vitro NASH models to evaluate the intervention effect of CEP. Subsequently, RNA-sequencing, western blotting, quantitative Real-Time PCR (qRT-PCR) and siRNA transfection were employed to investigate its underlying mechanisms.

Results: Our findings indicated that CEP significantly reduced lipogenesis and inflammatory responses in both HFD-fed rats and FFA-induced hepatic cells (including HepG2, L02 and AML12 cell lines), as is evidenced by the reduction of triglyceride (TG), lipid accumulation, and the release of inflammatory cytokines such as TNF-α, IL-6 and IL-1β. Mechanistically, CEP significantly inhibits CXC motif chemokine ligand 10 (CXCL10) expression both in vivo and in vitro. It also regulates sterol regulatory element binding protein-1c (SREBP1c)-induced lipogenic gene expression and CXCL10-mediated nuclear factor kappa B (NFκB) activation. Notably, knockdown of CXCL10 mimics the ability of CEP to reduce lipid accumulation and inflammatory responses, which is also observed following the blockade of signal transducer and activator of transcription 1 (STAT1) in HepG2 cells.

Conclusion: CEP alleviates NASH by inhibiting lipogenesis and inflammatory responses in a STAT1/CXCL10 axis-dependent manner.

Keywords
Cepharanthine; Inflammatory responses; Lipogenesis; Nonalcoholic steatohepatitis; STAT1/CXCL10 axis.
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