PVN–DMV–Liver Circuit Drives Hepatocellular Carcinoma Progression in the Context of Depression Comorbidity

Hepatocellular carcinoma (HCC) and depression frequently co-occur, yet whether and how depression affects HCC progression is unknown. Here, we show that stress-induced mouse depression models, chronic restraint stress and chronic social defeat stress, robustly promote orthotopic HCC growth, shorten survival, and increase tumor proliferative and invasive abilities. Mechanistically, comorbidity between HCC and depression hyper-activates the glutamatergic paraventricular-hypothalamic (GluPVN) → cholinergic dorsal motor nucleus of vagus (AChDMV) → liver circuit that amplifies intra-tumor acetylcholine (ACh). Single-cell transcriptomics identified an ACh-responsive epithelial sub-cluster expressing the nicotinic acetylcholine receptor (nAChR) subunit alpha-9 (Chrna9), which is up-regulated under the comorbid status. These Chrna9⁺ epithelial cells engage Cxcl1+ macrophages via a Col1a2–Cd44 axis, thereby stimulating further CXCL1 production. CXCL1 not only fuels tumor aggressiveness but also crosses the blood–brain barrier, acts on PVN neurons, and aggravates depression-like behaviors, thereby forming a liver-brain feedback loop. Chemogenetic or optogenetic silencing of the GluPVN→AChDMV→liver pathway, knockdown of Chrna9 in tumor cells, or neutralization of CXCL1 effectively restrained HCC progression in comorbid mice. Collectively, these results reveal that comorbidity-driven activation of the GluPVN→AChDMV→liver circuit remodels the hepatic immune micro-environment and uncover the Chrna9–Col1a2–Cd44–Cxcl1 cascade as a therapeutic target for patients with HCC–depression comorbidity.