Integrated Multi‐Omics Analysis Identifies HVCN1 as a Potential Mediator in Neuroendocrine–Tumor Interactions in Colorectal Cancer

ABSTRACT Objective To investigate associations among sleep‐related features, neuroendocrine alterations, and colorectal cancer (CRC)‐related molecular programs, and to identify candidate genes involved in hypothalamus–tumor interactions. Methods NHANES data were analyzed to assess associations between sleep disorder status and mortality among cancer survivors. An orthotopic MC38 CRC mouse model was used to evaluate sleep–wake and neuroendocrine alterations. Integrative analyses of murine hypothalamic and colorectal tissue transcriptomes, TCGA data, and public hypothalamic single‐cell datasets were performed to identify and characterize candidate genes. HVCN1 knockdown and overexpression were used for functional validation in MC38 cells. Results Sleep disorder status was inversely associated with cardiovascular mortality in NHANES cancer survivors (HR = 0.47, 95% CI: 0.29–0.74, p = 0.001), but not with all‐cause or cancer‐specific mortality. Tumor‐bearing mice exhibited sleep fragmentation‐like changes with increased corticosterone and norepinephrine levels. Transcriptomic integration identified 28 shared genes between hypothalamic and colorectal tissues, including HVCN1. TCGA analysis identified a sleep disturbance‐related CRC subtype with poorer survival, while single‐cell analysis revealed cell‐type‐dependent expression of HVCN1 across hypothalamic populations. HVCN1 was upregulated in hypothalamic and tumor tissues, and its overexpression promoted MC38 cell proliferation, migration, and invasion, whereas knockdown produced opposite effects. Conclusion Tumor‐bearing status is associated with coordinated sleep–wake, neuroendocrine, and molecular alterations. HVCN1 is a candidate component of the hypothalamus–tumor interaction framework and regulates aggressive CRC cell behaviors in vitro, while its proposed pH‐regulatory mechanism requires further validation.