- Dysregulation of the liver-nervous system axis, with sympathetic overactivation and parasympathetic hypofunction, centrally drives MASLD onset and progression.
- 'Brain-to-liver' and 'liver-to-brain' signalling form a reciprocal feedback loop that exacerbates systemic metabolic disturbance.
- Targeting the axis with pharmacological, neuromodulatory and behavioural interventions offers a promising mechanism-based therapeutic frontier for MASLD.
eGastroenterology. 2026 Aug 31;4(3):e100397. doi: 10.1136/egastro-2026-100397. eCollection 2026.
ABSTRACT
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.
PMID:42689015 | PMC:PMC13536109 | DOI:10.1136/egastro-2026-100397
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