2. Academic Validation
  3. Novel dual AMPK/NRF2 activation by leucocyanidin from Hawthorn (Crataegus) for mitochondria repair-Targeted therapy of hepatic steatosis

Novel dual AMPK/NRF2 activation by leucocyanidin from Hawthorn (Crataegus) for mitochondria repair-Targeted therapy of hepatic steatosis

  • Phytomedicine. 2025 Nov 27:150:157614. doi: 10.1016/j.phymed.2025.157614.
Yunheng Li 1,  Minghua Ye 1,  Qiaojun He 2,  Bo Yang 3,  Peihua Luo 4,  Xiaochun Yang 5
Affiliations

Affiliations

  • 1 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; School of Medicine, Hangzhou City University, Hangzhou 310015, China.
  • 3 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; School of Medicine, Hangzhou City University, Hangzhou 310015, China.
  • 4 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
  • 5 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
PMID: 41365192 DOI: 10.1016/j.phymed.2025.157614
Abstract

Background and purpose: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a global health challenge with limited therapeutic options. This study identified leucocyanidin (Leuc), a bioactive flavonoid from the traditional herb Crataegus pinnatifida (hawthorn), as a novel dual-target therapeutic agent against MASLD.

Methods and results: We evaluated the effects of Leuc on a mouse model induced by a 60% high-fat diet and a cell model induced by free fatty acids (FFA). Compared to the model group, Leuc treatment dose-dependently significantly reduced liver weight, serum levels of TG and TC, hepatic inflammation markers (IL-6 and TNF-α), as well as cellular TG content. Histological and fluorescence analyses revealed a significant reduction in lipid droplet accumulation. Mechanistically, Leuc exerted its protective effects through two major pathways: (1) By activating the NRF2 antioxidant axis, Leuc attenuated oxidative stress-induced mitochondrial dysfunction and restored fatty acid β-oxidation capacity; (2) Through direct allosteric binding to AMPK, Leuc suppressed fatty acid uptake, inhibited lipogenesis, and enhanced mitochondrial fatty acid transport.

Conclusion: These coordinated mechanisms reestablished hepatic lipid homeostasis, positioning Leuc as a promising dual-target natural compound for MASLD intervention through simultaneous AMPK/NRF2 activation.

Keywords

Fatty acid β-oxidation; Hawthorn; Leucocyanidin; Lipid homeostasis; MASLD; Mitochondrial dysfunction.

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