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
  • 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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