Anterior cingulate cortex mediates the comorbidity between colorectal cancer and depression-like behaviors.

Clinical studies demonstrate that comorbidity between colorectal cancer (CRC) and depression is common, leading to a higher mortality risk among CRC patients. However, the mechanisms remain largely unexplored. The role of core brain regions in comorbidity of CRC and depression and whether modulating these regions can improve both depression-like symptoms and CRC progression have yet to be clarified. In this study, we establish a mouse (Mus musculus) model of CRC and observe that mice with orthotopic colorectal cancer (CRC mice) display depression-like behaviors. Through c-FOS mapping, network analysis, correlation analysis, and inverse tracing, we identify the anterior cingulate cortex (ACC) as a central node within the depression-related brain network in CRC mice. Notably, inhibiting ACC activity not only alleviates depression-like behaviors but also mitigates CRC-induced neuronal damage and reduces CRC tumor progression. These findings underscore the critical role of the ACC in comorbidity of CRC and depression and suggest that ACC-targeted interventions may hold therapeutic potential for CRC patients with comorbid depression.