Abstract
Osteosarcoma lacks effective molecular targets, and the biological role of MAT2A in this disease remains unclear. Here we show that MAT2A drives osteosarcoma progression by increasing the transcription of the downstream gene PARN. MAT2A interacts with the transcription factor SRF, promotes its SUMO-dependent stabilization in the nucleus, and enhances its ability to activate PARN. A catalytically inactive MAT2A mutant retains this function, indicating a SAM-independent mechanism. MAT2A also elevates aerobic glycolysis in osteosarcoma cells through the PARN-PI3K-AKT pathway, while pharmacological inhibition of MAT2A reduces glycolysis, SRF and PARN expression, and tumor growth in vitro and in vivo. These findings identify a previously unrecognized regulatory mechanism linking MAT2A to transcriptional control and metabolic reprogramming, and highlight MAT2A as a promising therapeutic target for osteosarcoma.