2. Academic Validation
  3. Hinokitiol ameliorates MASH in mice by therapeutic targeting of hepatic Nrf2 and inhibiting hepatocyte ferroptosis

Hinokitiol ameliorates MASH in mice by therapeutic targeting of hepatic Nrf2 and inhibiting hepatocyte ferroptosis

  • Phytomedicine. 2025 Feb 5:139:156472. doi: 10.1016/j.phymed.2025.156472.
Xunzhe Yin 1,  Zuojia Liu 2,  Chang Li 3,  Jin Wang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, No.5625, Ren Min Street, Changchun, Jilin 130022, China; Center for Theoretical Interdisciplinary Sciences, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China.
  • 2 State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, No.5625, Ren Min Street, Changchun, Jilin 130022, China. Electronic address: zjliu@ciac.ac.cn.
  • 3 State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, No.5625, Ren Min Street, Changchun, Jilin 130022, China.
  • 4 Center for Theoretical Interdisciplinary Sciences, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China; Department of Chemistry and Physics, Stony Brook University, Stony Brook, New York 11794-3400, USA. Electronic address: jin.wang.1@stonybrook.edu.
PMID: 39922149 DOI: 10.1016/j.phymed.2025.156472
Abstract

Background: Metabolic dysfunction-associated steatohepatitis (MASH), an advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD), still lacks approved effective clinical drugs. Ferroptosis, a form of regulated cell death driven by excessive iron accumulation and uncontrollable lipid peroxidation, has been proven to be a trigger of inflammation and initiation of steatohepatitis. The pathogenic interplay is modulated by oxidative stress, while the Nrf2-mediated antioxidant response plays a regulatory role in Ferroptosis. Phytochemical hinokitiol (Hino) has demonstrated positive efficacy in hepatocellular carcinoma (HCC) in the reported work, but it remains unknown whether its therapeutic effect attributes to delaying the progress of steatohepatitis to HCC.

Purpose: This work aimed to systemically investigate the significance of Ferroptosis in the pathogenesis of MASH and to demonstrate that Hino, a bioactive monoterpene compound, attenuates the primary pathological characteristics of MASH via promotion of Nrf2/GPX4 signaling.

Methods: In this work, a MASH model was established using the high-fat/high-cholesterol (HFHC) diet-fed in vivo and palmitic acid/oleic acid (PO)-stimulated hepatocytes in vitro. Biochemical indexes, pathological analysis, western blot, PCR assay, energy metabolic phenotype, molecular docking, and confirmatory assays were performed comprehensively to reveal the key link between the Nrf2/GPX4 axis and the treatment of MASH.

Results: Under MASH conditions with increased oxidative stress, we show that Nrf2 was remarkable downregulated in HFHC diet-fed mice and PO-managed hepatocytes. Mechanistically, hepatic upregulation of Nrf2 through phytochemical Hino supplementation inhibited Ferroptosis, enhanced lipid metabolism, and thereby alleviated hepatic steatosis, inflammation, and fibrosis. Conversely, silencing Nrf2 in hepatocytes further promoted the accumulation of key markers of Ferroptosis and aggravated MASH phenotypes.

Conclusion: Increased Ferroptosis promoted steatosis which further drove inflammation and hepatic fibrosis. Our results suggested the significance of Nrf2 in ameliorating MASH, which was regulated through Hino. Thus, targeted inhibition of Ferroptosis through Hino administration is a feasible and effective approach for treating MASH.

Keywords

Hepatocyte ferroptosis; Hinokitiol; MASH; Nrf2; Oxidative stress.

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