Circadian and behavioral timing in MASLD: a systematic review of human observational studies.

BACKGROUND: Circadian disruption may affect metabolism through altered timing of sleep, activity, light exposure, hormonal rhythms, and food intake. However, its relationship with metabolic dysfunction-associated steatotic liver disease (MASLD), including fibrosis and cirrhosis remains unclear. To evaluate associations between circadian and behavioural timing exposures and MASLD in observational studies. METHODS: PubMed, Embase, and Scopus were searched from inception to 14 July 2026. Eligible studies examined naturally occurring timing-related exposures in adults and reported steatosis, fibrosis, cirrhosis, or quantitative liver-fat outcomes. Findings were synthesized narratively because heterogeneity precluded pooling. Risk of bias was assessed using AXIS or the Newcastle-Ottawa Scale, and certainty using an adapted domain-level GRADE approach (PROSPERO Registration number: CRD420261381636). FINDINGS: Twenty-four independent MASLD-related evidence sources were included in the primary synthesis; two additional mixed-aetiology cirrhosis studies were considered contextually. Shift work showed the most consistent associations and most longitudinal evidence. Chronotype was generally associated with disease occurrence but inconsistently with advanced outcomes: intermediate or late chronotype was associated with fibrosis in one clinical cohort, whereas morning chronotype was not independently associated with incident cirrhosis in a prospective cohort. Later sleep timing was associated with prevalent MASLD and, in one NHANES analysis, fibrosis. Evidence for objective rest-activity rhythms, light exposure, meal timing, and melatonin phase remained limited or heterogeneous. Mixed-aetiology cirrhosis studies suggested that advanced liver disease may itself disrupt circadian physiology. INTERPRETATION: Circadian and behavioural timing exposures showed trends associated with MASLD-related outcomes, with the most consistent evidence for shift work. Residual confounding, cross-sectional designs, self-reported exposures, heterogeneous outcomes, and reverse causality preclude causal conclusions. Prospective studies using objective circadian phenotyping and standardized fibrosis outcomes are needed. FUNDING: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.