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. Chronic stress can promote hepatocellular carcinoma (HCC) progression. Here, the authors show in mice that chronic stress activates a brain-liver signaling circuit that mediates tumor epithelial-macrophage crosstalk and promotes HCC growth.