2. Academic Validation
  3. Cannabidiol attenuates the LPS/D-Galactosamine-induced acute liver injury by inhibiting parkin-mediated ubiquitination of MFN2

Cannabidiol attenuates the LPS/D-Galactosamine-induced acute liver injury by inhibiting parkin-mediated ubiquitination of MFN2

  • J Ethnopharmacol. 2026 Mar 25:359:121067. doi: 10.1016/j.jep.2025.121067.
Zhikun Zhan 1,  Yaojie Jiang 1,  Siyu Chen 1,  Qiyuan Yang 1,  Guanxing Pan 2,  Yiwei Liu 1,  Weipeng Fang 1,  Runzhi Chen 3,  Lan Tang 4,  Cuihong Lin 5
Affiliations

Affiliations

  • 1 Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
  • 2 Clinical Pharmacology Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Clinical Pharmacology Research Center, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
  • 3 Key BioAI Synthetica Lab for Natural Product Drug Discovery, College of Bee and Biomedical Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China. Electronic address: [email protected].
  • 4 NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: [email protected].
  • 5 Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China. Electronic address: [email protected].
PMID: 41419044 DOI: 10.1016/j.jep.2025.121067
Abstract

Ethnopharmacological relevance: Acute liver injury (A-LI) is a clinical syndrome that can rapidly progress to acute liver failure, resulting in high mortality and poor prognosis. Cannabis sativa L. is an important herbaceous plant that has been widely used in folk medicine since ancient times. Cannabidiol (CBD) is its most abundant non-psychoactive compound, exhibiting hepatoprotective, anti-inflammatory, and antioxidant properties. However, the protective effect of CBD against A-LI and its mechanism remain unclear.

Objective: This study aimed to investigate the protective effects of CBD on A-LI and elucidate the underlying molecular mechanisms.

Methods: In vivo, an A-LI mouse model was induced by LPS/D-GalN. Each group was treated with or without LPS/D-GalN or CBD. H&E staining, alanine aminotransferase (ALT), aspartate aminotransferase (AST) level assay, TUNEL staining, TEM, IF, RT-qPCR, Western blot, Co-IP and adeno-associated virus (AAV) Infection were performed. In vitro, RAW264.7 cells were stimulated with LPS. CCK-8, ELISA, MMP, mitochondrial ROS assay, siRNA knockdown and plasmid overexpression were performed.

Results: CBD (2.5 or 5 mg kg-1) mitigated LPS/D-GalN-induced liver damage, suppressed inflammatory cytokine expression, reduced hepatocellular Apoptosis, and inhibited oxidative stress. CBD treatment increased hepatic mitofusin-2 (MFN2) protein while decreasing Parkin-MFN2 binding and MFN2 ubiquitination. In RAW264.7 cells, CBD pretreatment (2.5 or 5 μM) dose-dependently attenuated LPS-induced inflammation, Apoptosis, and mitochondrial dysfunction and likewise elevated MFN2 levels while limiting its ubiquitination. MFN2 knockdown abolished CBD's protective effects, whereas MFN2 overexpression restored them. Consistently, AAV-mediated delivery of MFN2-targeting short hairpin RNA reversed the hepatoprotective action of CBD in vivo.

Conclusion: CBD mediates anti-inflammatory and hepatoprotective effects by inhibiting MFN2 degradation through disrupting the interaction between Parkin and MFN2. These results provide molecular evidence for application of CBD in treatment of A-LI and provide references to the drug development for A-LI.

Keywords

Acute liver injury; Cannabidiol; LPS; Mitofusin-2; Parkin.

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