Mat1a, encoding S-adenosylmethionine (SAM) synthesizing isozymes MATI/III, is mainly expressed in the normal liver. MAT1A catalyzes the conversion of methionine and ATP to SAM, the principal biological methyl donor [2,4]. This process is crucial for one-carbon metabolism and intersects with epigenetic regulation [5].

In hepatocellular carcinoma (HCC), the downregulation of MAT1A, known as the MAT1A:MAT2A switch, contributes to a decrease in SAM level [2]. MAT1A-KO mice, characterized by chronic SAM deficiency, exhibit macrovesicular steatosis, mononuclear cell infiltration in periportal areas, and HCC development [2]. Also, in HCC, the CTBP1/HDAC1/HDAC2 transcriptional complex suppresses MAT1A transcription. MAT1A overexpression increases SAM levels, promoting ferroptosis of HCC cells and enhancing CD8+ T-cell cytotoxicity [3].

In non-small cell lung cancer (NSCLC), knockdown of MAT1A impedes cell proliferation and migration while enhancing apoptosis. MAT1A promotes NSCLC progression by stabilizing CCND1 to activate glycolytic pathways [1]. Moreover, in liver cancer metastasis, loss of MAT1A increases matrix metalloproteinase-7 (MMP-7) expression, promoting metastasis [6].

In conclusion, Mat1a is essential for SAM synthesis, with its deficiency in KO mouse models linked to various liver-related pathologies such as HCC, steatosis, and inflammation. In NSCLC, it plays a role in cancer cell proliferation and glycolysis. Understanding Mat1a through these model-based studies provides insights into the mechanisms of cancer development, offering potential targets for therapeutic intervention in liver and lung cancers.