Abstract

The liver-brain axis represents a complex and dynamic interface where hepatic metabolic processes influence central 
nervous system (CNS) function, and conversely, neural and neuroendocrine signals modulate liver physiology. This 
bidirectional communication is particularly relevant in the context of environmental toxicant exposure and 
metabolic disorders, including diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD), which collectively 
increase the burden of oxidative stress, inflammation, and metabolic dysregulation. Environmental toxicants such 
as heavy metals, pesticides, and persistent organic pollutants can impair hepatic detoxification and antioxidant 
defenses, leading to the release of pro-inflammatory cytokines, reactive metabolites, and neurotoxic intermediates 
into circulation, which adversely affect brain function. Simultaneously, neuroinflammation, altered autonomic 
signaling, and metabolic disturbances in the CNS can exacerbate liver injury, creating a feed-forward loop of organ 
cross-talk. Recent evidence highlights the potential of hepatoprotective and neuromodulatory interventions, 
including natural bioactive compounds, to restore redox balance, reduce inflammation, enhance detoxification 
pathways, and support neuronal resilience. Understanding the molecular mechanisms underlying liver-brain 
communication is critical for developing integrated therapeutic strategies that concurrently protect hepatic and 
neural health, mitigate environmental toxicant-induced damage, and reduce the risk of cognitive decline and 
neurodegenerative outcomes in populations with metabolic disorders.