We reveal previously unrecognized signaling axis for NAT10/ac4C-YTHDC1/m6A-LDHA/PFKM in osteosarcoma, suggesting that reprogramming RNA m6A methylation as a potential and promising strategy for osteosarcoma treatment, and providing profound insights into the molecular mechanisms underlying osteosarcoma development. Here, METTL3 is linked to osteosarcoma.