Depression-induced systemic C16-ceramide deficiency promotes OSCC via attenuation of mitochondrial apoptosis

Depression is a recognized risk factor for cancer progression, but the underlying metabolic mediators remain unclear. Here, we identify circulating C16-ceramide depletion as a key mechanism linking depression to oral squamous cell carcinoma (OSCC) progression. Mendelian randomization analysis first established a genetic causal link between depression and increased head and neck cancer risk. In mice, chronic stress, mimicking depression, accelerated orthotopic tongue tumor growth and concurrently reduced circulating levels of C16-ceramide. Exogenous restoration of C16-ceramide reversed this tumor-promoting effect. Mechanistically, C16-ceramide was taken up by OSCC cells via the scavenger receptor SCARB1, accumulated in mitochondria, and induced opening of the mitochondrial permeability transition pore (mPTP), thereby triggering mitochondrial apoptosis. Inhibition of mPTP opening abolished the anti-tumor effects of C16-ceramide. Clinically, a gene signature reflecting this C16-ceramide-mPTP-apoptosis axis was associated with favorable survival in OSCC patients. Our study reveals a novel metabolic pathway whereby depression promotes oral carcinogenesis by depleting a circulating tumor-suppressive lipid, highlighting the therapeutic potential of targeting the C16-ceramide-mPTP-apoptosis pathway.