This narrative review synthesises current evidence on the metabolic and hormonal drivers of MASLD and MASH progression — covering insulin/glucagon imbalance, adipose tissue dysfunction, de novo lipogenesis, mitochondrial failure, sex hormones, the gut–liver–adipose axis, and fibrogenic signalling — with a focus on how systemic dysfunction translates into hepatic inflammation and fibrosis.
Insulin–glucagon imbalance is identified as the central integrative driver of MASLD progression: chronic hyperinsulinaemia promotes de novo lipogenesis via Akt/mTORC1–SREBP1c and directly activates hepatic stellate cells, while impaired glucagon action limits lipid oxidation and amino acid disposal. Fibrosis stage (not inflammation) is the main predictor of clinical outcomes, and gluconeogenic flux correlates with fibrosis stage rather than steatosis degree. Approved therapies now include resmetirom (THR-β agonist) and semaglutide (GLP-1RA) for non-cirrhotic MASH with F2–F3 fibrosis.
- Narrative (not systematic) review; evidence synthesis is selective and not exhaustive. - Much gut-dysbiosis and sex-hormone data (including HRT for MASLD) is associative; prospective/interventional validation is lacking. - Causality between adipose tissue insulin resistance (Adipo-IR) and liver fibrosis in humans remains difficult to establish directly.
Clinicians managing MASLD/MASH should assess adipose tissue insulin resistance (Adipo-IR index) alongside standard liver metrics, as it independently predicts fibrosis severity and tracks response to thiazolidinediones. Resmetirom and semaglutide are now approved for non-cirrhotic MASH (F2–F3); dual/pan-incretin and PPAR agonist strategies are in late-stage trials and may offer broader metabolic benefits.
