Letter to the Editor: Circadian and microbial misalignment in metabolic dysfunction-associated steatotic liver disease - mechanistic insights and chronotherapeutic potential

Table 1 Circadian disruption and social jet lag as modifiers of associated steatotic liver disease pathogenesis and management

Domain	Circadian/SJL-related factor	MASLD-relevant mechanism	Ref.
Disease framework	Circadian regulation of metabolic homeostasis	Hepatic lipid handling, glucose metabolism, and inflammatory pathways are under circadian control; disruption amplifies insulin resistance and steatosis	[15,16]
Lifestyle modifiers	SJL	Persistent misalignment between endogenous clocks and behavioural schedules promotes metabolic inflammation independent of caloric excess	[5,7]
Gut-liver axis	Rhythmic intestinal barrier function	Tight junction proteins (occludin, claudin-1) show circadian oscillation; disruption increases permeability and endotoxin flux	[6,8]
Innate immunity	Circadian gating of immune responses	Toll-like receptor signalling varies by time of day; circadian disruption exaggerates inflammatory responses to microbial products	[10]
Gut microbiota	Temporal dysbiosis	Circadian disruption blunts microbial diurnal oscillations, impairing host–microbe metabolic signalling	[5,12]
Metabolite signalling	SCFAs as clock synchronisers	SCFAs (e.g., butyrate) entrain epithelial and hepatic clocks via HDAC inhibition; arrhythmic delivery weakens metabolic homeostasis	[11,13]
Bile acid metabolism	Circadian bile acid-FXR axis	Diurnal bile acid oscillations regulate hepatic lipid and glucose metabolism; disruption impairs FXR signalling	[14,18]
Human phenotype	Nocturnal metabolic vulnerability	MASLD associated with exaggerated nocturnal insulin resistance and reduced nighttime insulin availability	[15]
Dietary intervention	Time-restricted eating	Consistent eating windows restore hepatic and microbial rhythmicity, improving insulin sensitivity and reducing liver fat	[21,29]
Microbiota-targeted therapy	Circadian dependence of efficacy	FMT efficacy correlates with restoration of microbial rhythmicity	[23,29]
Adjunctive strategies	Chronobiotics (e.g., melatonin)	Chronobiotics can re-entrain host–microbial rhythms under circadian disruption	[22]
Research considerations	Timing as a biological confounder	Ignoring circadian timing may obscure biomarker interpretation and treatment effects	[5]

SJL: Social jet lag; MASLD: Associated steatotic liver disease; SCFAs: Short-chain fatty acids; HDAC: Histone deacetylase; FXR: Farnesoid X receptor; FMT: Fecal microbiota transplantation.