2. Academic Validation
  3. Cytochrome P450-mediated detoxification and NF-κB/NLRP3 pathway-driven hepatotoxicity of emodin: Multiomics and laboratory evidence

Cytochrome P450-mediated detoxification and NF-κB/NLRP3 pathway-driven hepatotoxicity of emodin: Multiomics and laboratory evidence

  • Chem Biol Interact. 2026 Mar 25:427:111934. doi: 10.1016/j.cbi.2026.111934.
Lili Wu 1,  Siyu Chen 2,  Qiyuan Yang 2,  Xing Li 3,  Lingyan Liu 2,  Shengjun Ji 1,  Shuaiyuan Tang 4,  Sihui Zhang 4,  Yan Wang 5,  Runzhi Chen 6,  Zhikun Zhan 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, The First People's Hospital of Foshan (Foshan Hospital Affiliated to Southern University of Science and Technology), School of Medicine, Southern University of Science and Technology, Foshan, 528000, China.
  • 2 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.
  • 3 Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 4 Key BioAI Synthetica Lab for Natural Product Drug Discovery, College of Bee and Biomedical Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.
  • 5 Department of Pharmacy, The First People's Hospital of Foshan (Foshan Hospital Affiliated to Southern University of Science and Technology), School of Medicine, Southern University of Science and Technology, Foshan, 528000, China. Electronic address: [email protected].
  • 6 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].
  • 7 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: 41579920 DOI: 10.1016/j.cbi.2026.111934
Abstract

Emodin, a bioactive compound abundant in Chinese medicinal herbs, possesses broad therapeutic potential but raises safety concerns due to conflicting reports of hepatotoxicity. This study investigated the toxicological mechanisms underlying emodin-induced liver injury. Emodin (25-100 μM) elicited dose-dependent cytotoxicity in HepG2 cells, with the Cytochrome P450 (CYP) Enzymes CYP1A2 and CYP3A4 identified as the primary Enzymes metabolizing emodin into hydroxylated products (M1-M3). The comparative cytotoxicity assay of emodin and its metabolites in HepG2 cells indicated that CYP-mediated metabolism functions as a critical detoxification pathway. Moreover, inhibition of CYP with 1-aminobenzotriazole (ABT, 500 μM) markedly enhanced emodin (12.5-100 μM) cytotoxicity in HepG2 cells. Similarly, ABT (50 mg/kg) markedly exacerbated emodin (400 mg/kg)-induced hepatotoxicity in mice following three weeks of co-administration. Transcriptomic profiling and validation experiments demonstrated that activation of the NF-κB/NLRP3 signaling axis contributes to emodin-induced hepatic injury. Metabolomic analyses further revealed perturbations in key pathways, including lipopolysaccharide (LPS) biosynthesis, sphingolipid metabolism, and Cholesterol metabolism. Integrated multi-omics analysis identified a significant positive correlation between these metabolites (LPS, sphingosine, Cholesterol) and NF-κB/NLRP3 pathway genes. These findings suggest that emodin-mediated upregulation of LPS, sphingosine, and Cholesterol activates the NF-κB/NLRP3 pathway, subsequently triggering hepatic injury. Collectively, this study delineates the metabolic detoxification routes of emodin and provides mechanistic insight into its hepatotoxic potential.

Keywords

CYP; Emodin; Hepatotoxicity; Metabolomics; NF-κB/NLRP3 pathway; Transcriptomics.

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