Metabolic dysfunction-associated steatotic liver disease (MASLD) has traditionally been viewed primarily through the lens of hepatic lipid accumulation, insulin resistance and metabolic dysfunction. A new review published in eGastroenterology proposes a broader perspective: the nervous system may be an active participant in both the initiation and progression of MASLD. The central message is that MASLD may involve a dysfunctional bidirectional “liver–nervous system axis”, rather than being solely a hepatocyte-centred metabolic disorder.
Professor Wang, Professor Li, and colleagues describe the liver as being connected to the central nervous system through sympathetic, parasympathetic and sensory pathways. Within this framework, sympathetic signalling functions as a metabolic “accelerator”, promoting hepatic glucose production, lipid metabolism disturbances and inflammatory responses, whereas parasympathetic (or vagal) signalling acts more like a “brake”, helping maintain metabolic and immune homeostasis. An imbalance characterised by sympathetic overactivation and parasympathetic withdrawal could therefore contribute to MASLD development and progression.
A vicious cycle linking the brain and liver
The review integrates evidence suggesting that excessive sympathetic activity can influence several key features of MASLD. Norepinephrine-mediated signalling may increase hepatic glucose production, promote adipose tissue lipolysis and increase the delivery of free fatty acids to the liver. Sympathetic neurotransmitters can also act on hepatic stellate cells and activate pathways including MAPK, PI3K and TGF-β signalling, potentially promoting fibrogenesis.
At the same time, impaired parasympathetic activity may weaken the cholinergic anti-inflammatory pathway. Reduced acetylcholine signalling through α7 nicotinic acetylcholine receptors on Kupffer cells may diminish suppression of NF-κB signalling and inflammatory cytokines such as TNF-α and IL-6. Importantly, the communication is not one-way. Hepatic steatosis, inflammation and altered metabolic signals can be transmitted back to the brain through vagal and humoral pathways, potentially affecting appetite, energy balance, cognition and emotional regulation. Conversely, chronic stress and altered central nervous system activity may reduce vagal tone, disturb the gut–brain–liver axis and further aggravate hepatic injury. Together, these mechanisms create a self-reinforcing loop in which metabolic liver injury and nervous system dysfunction may amplify one another.
Turning neural circuits into therapeutic targets
This framework also opens new therapeutic possibilities. The authors highlight several potential approaches: reducing excessive sympathetic tone, enhancing parasympathetic signalling, using vagus nerve stimulation, and targeting neuro-metabolic pathways with GLP-1 receptor agonists, multi-incretin agonists and FGF21-based therapies. Diet, physical activity and stress management may additionally influence autonomic balance and therefore form an integral part of this therapeutic concept. Rather than treating liver fat alone, future therapies could potentially restore the broader neuro-metabolic balance connecting the brain, liver, adipose tissue and gut.
Important gaps before clinical translation
The authors nevertheless emphasise that this field remains at an early translational stage. One major concern is the substantial difference between human and rodent hepatic innervation. Human livers contain intralobular sympathetic fibres, whereas such fibres are largely absent from rodent liver parenchyma, meaning that findings from denervation, chemogenetic and optogenetic experiments cannot automatically be extrapolated to patients.
Dedicated clinical trials with liver-specific outcomes are also limited, while practical biomarkers of neuro-metabolic dysfunction remain underdeveloped. Future priorities therefore include validation in models that better resemble human hepatic innervation, improved patient stratification, multi-omics biomarker discovery and trials examining histological, metabolic and neurological outcomes.
Overall, the review positions the liver–nervous system axis as a potentially important new dimension of MASLD biology. If supported by human mechanistic studies and clinical trials, targeting this axis could ultimately shift MASLD management from an exclusively liver-focused strategy towards more integrated regulation of systemic metabolic homeostasis.
See the article s
Wang X, Zhang J, Guo J, et al . Liver-nervous system axis in MASLD: mechanistic insights and emerging targeted therapies. eGastroenterology 2026; 4 :e100397. doi:10.1136/egastro-2026-100397
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Liver-nervous system axis in MASLD: mechanistic insights and emerging targeted therapies