2. Academic Validation
  3. Myricetin stabilizes PINK1 to activate mitophagy and ameliorate metabolic dysfunction-associated steatotic liver disease

Myricetin stabilizes PINK1 to activate mitophagy and ameliorate metabolic dysfunction-associated steatotic liver disease

  • Phytomedicine. 2026 Jun:155:158009. doi: 10.1016/j.phymed.2026.158009.
Weilong Xu 1,  Lijuan Nie 2,  Jing Cao 3,  Chuchu Shan 4,  Yutian Cao 4,  Jialin Yu 5,  Pengxu Tuo 6,  Jiangyi Yu 7,  Hideki Fujii 8,  Le Thi Thanh Thuy 9,  Fei Li 10,  Xiqiao Zhou 11
Affiliations

Affiliations

  • 1 Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: [email protected].
  • 2 Science and Education Department, Affiliated Psychological Hospital of Anhui Medical University, Hefei Fourth People's Hospital, Hefei 230032, China.
  • 3 Department of General Internal Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China.
  • 4 Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China; The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 5 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 6 The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 7 Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China.
  • 8 Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan.
  • 9 Department of Global Education and Medical Sciences, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan.
  • 10 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
  • 11 Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China. Electronic address: [email protected].
PMID: 41935459 DOI: 10.1016/j.phymed.2026.158009
Abstract

Background: Myricetin, a bioactive flavonoid from Abelmoschus manihot, has demonstrated therapeutic potential for metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). However, its precise mechanisms, particularly concerning mitochondrial homeostasis, remain inadequately elucidated.

Objectives: The present study evaluated the therapeutic efficacy of myricetin in alleviating hepatic steatosis, inflammation, fibrosis, and Insulin resistance associated with MASLD/MASH, with a specific focus on unraveling the role of Mitophagy regulation.

Methods: MASLD and MASH models were established in mice using a high-fat diet (HFD) or a Gubra-Amylin NASH (GAN) diet, followed by myricetin treatment. Systemic metabolism, liver injury, histology, and Insulin sensitivity were assessed. Transcriptomic profiling was performed to analyze metabolic pathways. Molecular docking, surface plasmon resonance (SPR), co-immunoprecipitation, and immunofluorescence were used to study the interaction between myricetin and PINK1 and its impact on PINK1/Parkin-mediated Mitophagy. Finally, in vitro loss-of-function experiments using shPINK1 were conducted to validate the mechanism.

Results: Myricetin significantly ameliorated hepatic steatosis, inflammation, fibrosis, and systemic Insulin resistance in MASLD/MASH mice. Transcriptomics revealed enhanced fatty acid β-oxidation and mitochondrial function. Mechanistically, myricetin directly bound to PINK1, inhibiting its mitochondrial import through the TOM complex (TOM40) and subsequent cleavage by the PARL protease, thereby stabilizing PINK1 on the outer mitochondrial membrane. This stabilization activated PINK1/Parkin-dependent Mitophagy, restoring mitochondrial integrity. Notably, the myricetin-mediated improvements in Mitophagy and mitochondrial function were negated by PINK1 silencing.

Conclusion: Myricetin mitigates MASLD/MASH progression by acting as a novel PINK1 stabilizer, augmenting PINK1/Parkin-dependent Mitophagy to enhance mitochondrial quality. This study highlights myricetin as a potent intervention targeting mitochondria to combat metabolic liver diseases.

Keywords

Metabolic dysfunction-associated steatotic liver disease; Mitochondrial function; Mitophagy; Myricetin; PINK1 stability.

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