This narrative review highlights the systemic metabolic nature of nonalcoholic steatohepatitis (NASH), now reclassified as metabolic dysfunction-associated steatohepatitis (MASH). NASH is a multifactorial disease influenced by genetic, epigenetic, and environmental factors, including insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, and hypoxia. The high heterogeneity of NASH, driven by variable genetic backgrounds, exposure to metabolic stresses, and differences in repair responses, necessitates personalized medicine approaches. Lifestyle changes are the cornerstone of NASH therapy, but several trials have failed to identify effective pharmacological treatments. The review examines the epidemiological burden of NASH, its association with type 2 diabetes (T2D), obesity, and metabolic syndrome, and the limitations of histological endpoints in clinical trials. It also discusses the need for noninvasive biomarkers and a more holistic approach that includes cardiovascular, kidney, and metabolic outcomes. The review concludes by emphasizing the urgent need for research on noninvasive biomarkers and a more comprehensive assessment of systemic determinants, modifiers, and correlates of NASH to advance therapeutic development.This narrative review highlights the systemic metabolic nature of nonalcoholic steatohepatitis (NASH), now reclassified as metabolic dysfunction-associated steatohepatitis (MASH). NASH is a multifactorial disease influenced by genetic, epigenetic, and environmental factors, including insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, and hypoxia. The high heterogeneity of NASH, driven by variable genetic backgrounds, exposure to metabolic stresses, and differences in repair responses, necessitates personalized medicine approaches. Lifestyle changes are the cornerstone of NASH therapy, but several trials have failed to identify effective pharmacological treatments. The review examines the epidemiological burden of NASH, its association with type 2 diabetes (T2D), obesity, and metabolic syndrome, and the limitations of histological endpoints in clinical trials. It also discusses the need for noninvasive biomarkers and a more holistic approach that includes cardiovascular, kidney, and metabolic outcomes. The review concludes by emphasizing the urgent need for research on noninvasive biomarkers and a more comprehensive assessment of systemic determinants, modifiers, and correlates of NASH to advance therapeutic development.