Metformin-phytochemical combination therapy in metabolic dysfunction-associated steatotic liver disease: mechanistic...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial metabolic disorder characterized by excessive hepatic lipid accumulation, insulin resistance, oxidative stress, and chronic inflammation. Its pathogenesis spans interconnected metabolic, inflammatory, and fibrotic pathways, limiting the efficacy of single-target therapeutic approaches. Metformin (MET), a first-line antidiabetic agent, improves hepatic lipid metabolism primarily through AMPK activation and enhanced fatty acid oxidation; however, its therapeutic impact on inflammatory and redox pathways remains limited, and its use is frequently associated with gastrointestinal adverse effects. In this context, phytochemicals-diverse plant-derived bioactive compounds with pleiotropic metabolic and antioxidant properties-have emerged as promising adjuncts to MET to achieve broader pathway coverage. For the first time, this comprehensive review evaluates preclinical in vivo evidence on metformin-phytochemical combination therapy in in vivo models of MASLD, with a specific focus on its mechanistic and therapeutic advantages over monotherapy. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar. Only original preclinical in vivo studies evaluating the combination of metformin with an isolated phytochemical in animal models of MASLD were included. Data were extracted on compound identity, dosing regimens, experimental models, and metabolic, inflammatory, and signaling outcomes. Across eligible studies, metformin-phytochemical combinations consistently demonstrated superior efficacy compared with monotherapy in reducing hepatic steatosis, oxidative stress, and inflammatory mediators. Combinations involving berberine, chlorogenic acid, genistein, malvidin, morin, silymarin, and p-coumaric acid were associated with improved energy metabolism and fatty acid β-oxidation, alongside suppression of lipogenesis and fibrotic signaling. Additional benefits reported across studies included modulation of adipose tissue metabolism, enhancement of autophagy-related pathways, and favorable effects on gut-liver axis signaling, depending on the phytochemical class and experimental context. Overall, the preclinical in vivo evidence indicates that metformin-phytochemical cotherapy provides a multipathway modulatory framework integrating metabolic, anti-inflammatory, and antifibrotic effects. These findings support the translational potential of this combination strategy; however, well-designed clinical studies are required to assess pharmacokinetic compatibility, optimize dosing ratios, and determine its relevance in human MASLD.