When the Liver Flares: Inflammatory and Immunometabolic Mechanisms Driving the Transition from MASLD to MASH

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is steadily increasing worldwide, primarily due to the ongoing obesity pandemic. Although MASLD may initially present as a relatively benign condition, it has the potential to progress to metabolic dysfunction-associated steatohepatitis (MASH), a more severe form that can lead to cirrhosis and hepatocellular carcinoma (HCC). A variety of factors contribute to the pathogenesis of MASLD, including gut dysbiosis, insulin resistance, dyslipidemia, lipotoxicity, and oxidative stress. Among these, recent evidence highlights chronic inflammation as a key driver of disease progression toward advanced stages. Global scientific efforts have begun to uncover the molecular mechanisms sustaining the inflammatory response in MASLD, although these pathways remain only partially understood. Furthermore, therapeutic options for MASLD and MASH are currently limited, with no approved pharmacological treatments available for the advanced stages of the disease. This review aims to provide a comprehensive overview of the current understanding of the cellular and molecular mechanisms involved in the inflammatory processes underpinning MASLD and MASH while also outlining the key challenges that lie ahead in the development of effective therapies.