Mesenchymal stem cells and extracellular vesicles for MAFLD: from biological mechanisms to translational prospects

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent metabolic disorder that can progress from simple steatosis to chronic inflammation and fibrosis. Currently, pharmacological agents for MAFLD remain limited, and lifestyle-based management often fails to halt disease progression, underscoring the need for multitarget therapeutic strategies. Mesenchymal stem cells (MSCs) represent a promising regenerative and immunomodulatory therapy capable of reprogramming the hepatic inflammatory microenvironment, improving metabolic homeostasis, and limiting fibrogenesis. Increasing evidence indicates that MSC efficacy is largely mediated through paracrine mechanisms, with MSC-derived small extracellular vesicles (MSC-EVs) acting as key effectors by delivering functional cargos, including microRNAs (miRNAs) and proteins. MSC-EVs attenuate inflammation via inflammasome inhibition and macrophage polarization, restore insulin sensitivity and lipid handling through AMP-activated protein kinase (AMPK)-associated metabolic signaling, and also limit fibrogenesis by suppressing hepatic stellate cell (HSC) activation as part of their integrated multitarget actions. This review integrates current insights into MAFLD pathogenesis and the therapeutic mechanisms of MSCs and MSC-EVs, and highlights translational priorities for their clinical development.