Liver-nervous system axis in MASLD: mechanistic insights and emerging targeted therapies

The pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) extends beyond intrinsic hepatic metabolic defects, involving critical bidirectional communication between the liver and the central nervous system-termed the liver-nervous system axis. This review proposes that dysregulation of this axis, characterised by sympathetic overactivation and parasympathetic hypofunction, is a central driver of MASLD onset and progression. We review the 'brain-to-liver' and 'liver-to-brain' signalling pathways, highlighting how their disruption forms a reciprocally detrimental feedback loop that exacerbates systemic metabolic disturbance. Furthermore, we summarise preclinical and clinical evidence to demonstrate that targeting this axis, through pharmacological, neuromodulatory or behavioural interventions, represents a promising therapeutic frontier. By moving beyond traditional paradigms, this approach offers a novel framework for the mechanism-based management of MASLD across disease stages.