Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): From Steatosis to Systemic Metabolic Failure: Classical Pathophysiology, Emerging Systemic Mechanisms and Modifiable Lifestyle Determinants

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the hepatic manifestation of systemic metabolic dysfunction and has emerged as one of the leading causes of chronic liver disease worldwide. Its pathogenesis is complex and multifactorial, involving insulin resistance, altered lipid metabolism, mitochondrial dysfunction, oxidative stress, and chronic low-grade inflammation. Beyond these classical mechanisms, growing evidence highlights the central role of modifiable lifestyle-related factors, including chronic positive energy balance, high intake of fructose and saturated fats, ultra-processed foods, physical inactivity, sleep disruption, and environmental exposures such as endocrine-disrupting chemicals and air pollution, which have been associated with the activation of lipogenic and proinflammatory pathways in preclinical and observational studies. Conversely, protective dietary patterns, particularly the Mediterranean diet, together with regular physical activity, exert hepatoprotective metabolic and anti-inflammatory effects. An extensive literature search was conducted across the PubMed, Scopus, Cochrane Library, and Embase databases, covering publications through June 2026. The review was conducted following the SANRA recommendations for narrative reviews. The inclusion criteria encompassed clinical trials, systematic reviews, meta-analyses, and international clinical practice guidelines. This review provides an integrated framework by linking in a single interpretative model the classical pathogenic pathways with emerging dietary, behavioral, and environmental determinants and with systemic interorgan communication networks involving hepatokines, adipokines, and myokines. Understanding MASLD as a multisystemic metabolic disease driven by multiple determinants has critical implications for the development of targeted preventive and therapeutic strategies aimed at reducing its global burden and prevalence.