Flavonoids as Modulators of Gut-Liver Axis: Emerging Therapeutic Strategies for MAFLD

Mengxuan Hao^1,2,3Zihui Wang^1,2Liren Wang⁴Aidiya Yimamu^1,2Xiaoling Su^1,2Minmin Zhang⁵Xinchan Li^1,2Quanlong Zhang^6*Zeyu Sun^1,2*

• ¹China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, HangZhou, China
• ²Yuhang Institute for Collaborative Innovation and Translational Research in Life Sciences and Technology, HangZhou, China
• ³Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, HangZhou, China
• ⁴College of Pharmaceutical Sciences, Zhejiang University, HangZhou, China
• ⁵Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
• ⁶College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, HangZhou, China

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant global health challenge affecting approximately 25% of adults worldwide. Given the limited efficacy of existing therapies, there is an urgent need for novel treatment strategies. Flavonoids, a diverse class of natural polyphenolic compounds, exhibit significant potential in ameliorating MAFLD by modulating hepatic lipid metabolism and immune-inflammatory responses via gut-liver axis. This review systematically explores the interactions between flavonoids and gut microbiota, elucidating their role in MAFLD progression. We highlight how flavonoid structural diversity and microbial biotransformation modulate multiple key pathways, such as PPARα, PPARγ, ERβ, Nrf2, NF-κB, and FXR signalling. These multi-target mechanisms underpin the therapeutic potential of flavonoids in reducing lipid accumulation, oxidative stress, inflammation, and fibrosis in MAFLD. We also discuss innovative strategies, including flavonoid-probiotic synergies, nanotechnology-enhanced delivery systems, and personalized nutrition strategies. By integrating evidence from preclinical models and clinical trials, we highlight the translational potential of flavonoid-based interventions for MAFLD management. Our analysis underscores flavonoids as multi-target, safe and effective solutions for MAFLD management, warranting further clinical studies to translate these findings into routine clinical practice.