Chronic stress activates a hypothalamic vagal circuit to promote hepatocellular carcinoma progression in male mice.

Hepatocellular carcinoma and depression frequently co-occur, yet the mechanisms linking them remain unclear. Here, we show that chronic stress, systemic inflammation, or neuropathic pain are associated with hepatocellular carcinoma progression in male mice. Chronic stress hyperactivates a glutamatergic paraventricular hypothalamic nucleus → cholinergic dorsal motor nucleus of the vagus → liver circuit, increasing intratumoral acetylcholine. Single-cell transcriptomics identifies acetylcholine-responsive Chrna9+ epithelial cells that interact with macrophages through COL1A1/2-CD44-STAT3 signaling to promote CXCL1 production. Acetylcholine also promotes tumor cell proliferation through CHRNA9. Circulating CXCL1 crosses the blood-brain barrier and activates hypothalamic glutamatergic neurons, exacerbating depression-like behaviors and establishing a liver-brain feedback loop. Silencing the hypothalamic vagal circuit, tumor-specific Chrna9 knockdown, or systemic CXCL1 neutralization restrains tumor progression and alleviates depression-like behaviors. These findings identify a neural and immune mechanism linking chronic stress to hepatocellular carcinoma progression in male mice.