Circadian disruption in metabolic dysfunction-associated steatotic liver disease: From hepatic clock remodeling to chronotherapeutic strategies

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Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multisystem metabolic disorder characterized by hepatic steatosis and cardiometabolic risk factors.Its initiation and progression involve insulin resistance, disrupted hepatic lipid flux, mitochondrial dysfunction, impaired gut-liver communication, and chronic low-grade inflammation.Evidence suggests that circadian disruption may be a temporal regulatory layer, rather than merely a concomitant feature of MASLD, linking shift work, sleep disturbance, aberrant light exposure, and mistimed food intake to hepatic metabolic injury.Interlocking transcriptional and translational feedback loops allow central and hepatic clocks to coordinate daily glucose and lipid metabolism, mitochondrial quality control, bile acid homeostasis, redox defense, and immune repair.Alterations in clock phase, amplitude, period, or interorgan synchrony may create temporal discordance among lipid synthesis, oxidation, and export.Experimental evidence suggests that such temporal disruption can contribute to hepatic lipid accumulation, inflammation, and fibrogenic processes, whereas direct causal evidence linking circadian disruption to fibrosis progression in humans remains limited.This review synthesizes clinical and experimental evidence linking shift work, sleep disturbance, and mistimed eating to MASLD; delineates how core positive, negative, and auxiliary clock circuits, hepatic metabolic rhythms, gut-liver communication, and immunometabolic rhythms contribute to disease initiation and progression; and critically assesses chronotherapeutic approaches, including timerestricted eating, exercise timing, restoration of sleep and light rhythms, optimized drug administration timing, and direct targeting of the molecular clock.