Disease and Health Research: Recent Developments Vol. 3

Non-alcoholic fatty liver disease (NAFLD), now largely encompassed by metabolic dysfunction-associated steatotic liver disease (MASLD), is a heterogeneous disorder in which common cardiometabolic exposures interact with genetic susceptibility, hepatocellular stress and tissue repair responses. This critical narrative review integrates historical NAFLD evidence with the contemporary MASLD framework and evaluates advances in pathophysiology, diagnosis, risk stratification and treatment through 5 July 2026. Literature was identified through live searches of major open scholarly sources, citation chaining and verification of relevant practice guidance and regulatory information. The evidence supports a shift from a steatosis-centred concept towards fibrosis-centred prognosis and phenotype-specific management. Insulin resistance, excess fatty-acid delivery, de novo lipogenesis, lipotoxicity, organelle stress, inflammatory signalling and hepatic stellate-cell activation form interacting rather than strictly sequential pathogenic processes; genetic variants and gut-liver signalling further modify risk, but neither currently supports routine precision treatment. For diagnosis, single tests are insufficient. Sequential non-invasive assessment, typically beginning with a simple blood-based fibrosis score and escalating to elastography or specialised biomarkers, offers a pragmatic strategy for identifying advanced fibrosis while limiting liver biopsy. Lifestyle intervention remains foundational, with weight reduction and exercise improving steatosis and, when sufficiently sustained, histological activity; long-term implementation is the principal limitation. The therapeutic landscape has changed materially: resmetirom and semaglutide provide disease-directed options for selected adults with non-cirrhotic MASH and F2-F3 fibrosis in the United States, whereas several incretin, pan-PPAR and fibroblast growth factor 21 programmes remain investigational. Important uncertainties persist regarding hard clinical outcomes, optimal treatment sequencing and combination, non-invasive monitoring of response, cirrhosis, lean phenotypes, paediatric disease, long-term safety and equitable access. The strongest current strategy is therefore integrated: identify patients at meaningful fibrosis risk, treat cardiometabolic drivers intensively, deploy disease-directed therapy selectively, and avoid assuming that short-term histological improvement is equivalent to prevention of decompensation, cancer or death.