Modulation of mitochondrial biogenesis by flavonoids via SIRT1 signalling in metabolic syndrome: a systematic review.

Metabolic syndrome (MetS) is a complex cluster of metabolic abnormalities, including insulin resistance, central obesity, dyslipidemia, and hypertension. Dysregulated mitochondrial biogenesis has emerged as a key pathogenic feature of MetS, while flavonoids are increasingly recognised for their ability to modulate mitochondrial function through SIRT1-dependent pathways. This review aims to critically evaluate the role of flavonoids in modulating mitochondrial biogenesis via SIRT1 signalling in MetS, with emphasis on mechanistic evidence. A systematic review was conducted with a mechanistic focus, integrating preclinical and translational evidence to assess the role of flavonoids in MetS through SIRT1. A comprehensive literature search was performed in PubMed, Scopus, and Web of Science up to 2025 using the keywords “flavonoids,” “flavonols,” “SIRT1,” “AMPK,” “GLUT4,” and “metabolic syndrome.” Flavonols have emerged as the most extensively studied subclass of flavonoids in MetS models, with compounds such as quercetin, myricetin, and luteolin demonstrating consistent protective effects. These effects were mediated by AMPK activation, GLUT4 translocation, and mitochondrial biogenesis via SIRT1 signalling, thereby improving insulin resistance, dyslipidemia, and mitochondrial dysfunction. Despite robust mechanistic evidence, no clinical trials to date have evaluated flavonols in the context of MetS. Limitations, such as poor bioavailability, pharmacokinetic variability, and the absence of standardised formulations, continue to hinder their clinical translation. To overcome translational barriers, future research should prioritise randomised controlled trials, alongside innovative strategies such as nanoformulations, microbiome-targeted interventions, and flavonoid-inspired therapeutics. Addressing these gaps could establish the flavonoid–SIRT1 axis as a novel therapeutic avenue for MetS.