A neuro-immune axis controls obesity-induced liver inflammation and cancer progression

About This Grant

Abstract Obesity-driven hepatocellular carcinoma (HCC) represents the final stage of metabolic dysfunction–associated steatotic liver disease (MASLD), a progressive liver disorder that advances from steatosis to steatohepatitis (MASH), fibrosis, and ultimately liver cancer. Although the liver lacks intrinsic neurons, it receives extensive autonomic innervation that contributes to the regulation of hepatic metabolism and immune function. Emerging evidence from our group and others suggests that hepatic neural integrity is progressively compromised during MASLD progression in both patients and experimental models. However, the contribution of obesity-associated neural injury to chronic liver inflammation and hepatocarcinogenesis remains poorly understood. This project will investigate a previously unrecognized neuroimmune mechanism that maintains hepatic immune homeostasis and protects against liver disease progression. Our preliminary studies suggest that disruption of communication between the nervous and immune systems in the liver promotes inflammatory responses that accelerate tumor development in obesity. We hypothesize that obesity-induced loss of hepatic neural regulation alters macrophage function, resulting in persistent inflammation, progression of steatohepatitis, and increased susceptibility to HCC. To test this hypothesis, Aim 1 will define how obesity-associated disruption of hepatic neuroimmune communication contributes to liver tumor development using complementary experimental models and human liver specimens. Aim 2 will determine the immune mechanisms through which neural regulation restrains inflammation and suppresses hepatocarcinogenesis. Mouse models are essential for these studies because they permit investigation of complex neuroimmune interactions within the intact liver microenvironment and enable longitudinal assessment of disease progression from steatosis to HCC, processes that cannot be directly studied in humans or reproduced in cultured cells. Completion of this exploratory study will establish a novel conceptual framework linking hepatic neuroimmune dysfunction to obesity-associated liver cancer and may identify new strategies for preventing or treating HCC in patients with MASLD.