Melatonin partially restores hepatic nocturnin oscillations in experimental models of MASLD

Melatonin, a pleiotropic neurohormone, is recognized for its hepatoprotective role in metabolic dysfunction-associated steatotic liver disease (MASLD) triggered by diet and/or chronodisruption. Nocturnin (Noct), a circadian clock output regulating hepatic lipid metabolism, has an unclear role in MASLD. This study explores circadian oscillations of Noct in MASLD and its synergy with melatonin. Differential gene expression analysis identified key lipogenic genes (HNF-4A and SCD) as targets of Noct enzymatic activity. Male C57BL/6J mice were subjected to high-fat-high-fructose (H) diet with or without chronodisruption (CD) for 16 weeks. Noct mRNA peaked at ZT12 in Control and H groups, while CD and HCD groups showed peaks at ZT6, alongside increased % relative amplitude, cumulative expression, and shifted Centre of Gravity (CoG). Melatonin treatment in H, CD, and HCD groups significantly reduced Noct amplitude and cumulative expression. In OA-treated HepG2 cells, Noct mRNA and protein levels rose at 36 h and 32 h, respectively, with CoG shifts. Melatonin reduced Noct mRNA but increased protein levels while correcting rhythmicity. Collectively, MASLD induces elevation and phase shifts in hepatic Noct expression, and melatonin demonstrates corrective effects on Noct circadian phasing, underscoring its therapeutic potential.