The mediator subunit complex protein MED15 promotes lipid deposition and cancer progression during hypoxia.

Hypoxia, a hallmark of solid tumors, is associated with increased lipid droplet (LD) accumulation. However, the mechanisms underlying this remain elusive. Here, we identify Mediator complex subunit 15 (MED15) as a critical regulator of hypoxia-inducible factor (HIF) signaling, potentially impacting LD accumulation. In mammalian cells, we elucidated that MED15, as a HIF target gene, participates in promoting HIF transcriptional activity without affecting HIFα protein levels, creating a positive feedback loop. Furthermore, zebrafish deficiency in med15 displayed decreased HIF activity and impaired tolerance to hypoxic stress. Functionally, MED15 deficiency attenuated the proliferation of colon and renal cancer cells in vitro and tumor growth in vivo. Mechanistically, MED15 acts upstream of carnitine palmitoyltransferase 1A (CPT1A), a key enzyme in fatty acid oxidation, ultimately promoting HIF-mediated LD accumulation. Disrupting the MED15-CPT1A axis impairs this process. These findings reveal a novel MED15-HIF-CPT1A axis that promotes LD formation, potentially contributing to hypoxic tumor progression.