DDX49 drives colorectal cancer progression by remodeling mitochondrial oxidative phosphorylation via PGC-1α binding

Colorectal cancer (CRC) is a highly prevalent and aggressive malignancy worldwide. Dysregulation of mitochondrial metabolic homeostasis critically contributes to CRC progression, yet the underlying regulatory mechanisms remain incompletely characterized. Using multi-omics analyses, we demonstrate that enhanced mitochondrial oxidative phosphorylation (OXPHOS) is a prominent metabolic feature of CRC, and identify the DEAD-box helicase DDX49 as a novel regulator of mitochondrial metabolism. DDX49 is aberrantly upregulated in CRC tissues, and its high expression correlates with advanced clinicopathological stages and adverse patient prognosis. In vitro and in vivo assays showed that DDX49 promotes CRC cell proliferation, clonogenicity, tumor growth and suppresses cellular apoptosis. Mechanistically, nuclear DDX49 directly binds to and stabilizes peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), which in turn upregulates TFAM and OXPHOS complex subunits, thereby enhancing mitochondrial respiratory function. Rescue assays further confirm that PGC-1α serves as an essential downstream mediator of DDX49. Collectively, our study reveals that DDX49 drives CRC progression via the DDX49–PGC-1α–OXPHOS regulatory axis, and highlights DDX49 as a promising prognostic biomarker and therapeutic target for CRC.