Mat2a, or Methionine Adenosyltransferase 2A, is a rate-limiting enzyme in the methionine cycle. It mainly catalyzes the synthesis of S-adenosylmethionine (SAM) from methionine and adenosine triphosphate (ATP). By controlling the balance of the cellular methionine metabolite pool, Mat2a regulates crucial steps in metabolism and the epigenetic control of transcription [1,3].

In MTAP-deleted cancers, Mat2a was identified as a synthetic lethal target. Inhibition of Mat2a substantially reduces SAM levels, shows antiproliferative activity in MTAP-deleted cancer cells and tumors, and is linked to reduced PRMT5 activity and splicing perturbations, along with DNA damage and mitotic defects [2]. In H3K27M mutant glioma, MAT2A represents a vulnerability as its depletion induces global depletion of H3K36me3, perturbing oncogenic and developmental transcriptional programs [4]. In osteosarcoma, MAT2A inhibits ferroptosis, and its knockdown promotes cell ferroptosis [5]. In osteoclastogenesis, inhibition of MAT2A suppresses osteoclast formation and function, preventing OVX-induced bone loss [6]. In skeletal muscle, impaired MAT2A expression or activity compromises the regeneration and repair capabilities, partially through p53-Fas-mediated apoptosis [7].

In conclusion, Mat2a plays essential roles in multiple biological processes and diseases. Studies using loss-of-function models, such as those in MTAP-deleted cancers, H3K27M mutant glioma, osteosarcoma, osteoclastogenesis, and skeletal muscle repair, have revealed its significance in metabolism, epigenetic regulation, cell proliferation, and cell death. These findings provide potential therapeutic targets for related diseases.