{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMethionine adenosyltransferase IIα (MAT2A) is a ubiquitously expressed enzyme that catalyzes the formation of S‐adenosylmethionine (SAM), the principal methyl donor essential for DNA, RNA, protein, and lipid methylation. Unlike its liver‐specific counterpart MAT1A, MAT2A expression is linked to cellular growth and adaptive metabolic responses. Early studies demonstrated that MAT2A expression is transcriptionally regulated by methionine availability and is associated with proliferative as well as dedifferentiated phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " In addition, dynamic modulation of MAT2A mRNA stability and half‐life in response to methionine withdrawal and salvage pathway activity further underscores its role in maintaining SAM homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent work has revealed a complex post‐transcriptional regulatory network governing MAT2A expression. Its mRNA harbors conserved hairpin structures in the 3′ untranslated region that are methylated by the N^6‐adenosine methyltransferase METTL16, thereby promoting efficient splicing and influencing RNA stability in accordance with intracellular SAM concentrations. These regulatory events have been linked to metabolite‐responsive intron detention as well as to mRNA decay mechanisms that fine‐tune SAM biosynthesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": " Furthermore, additional RNA‐binding proteins and microRNAs have been shown to modulate MAT2A levels, highlighting the enzyme’s pivotal role in metabolic adaptation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDeregulated MAT2A expression is a common feature in diverse malignancies such as hepatocellular carcinoma, colon, and breast cancers. Elevated MAT2A not only maintains intracellular SAM levels to promote methylation‐dependent oncogenic signaling (for example via PRMT5 pathways) but also contributes to chemoresistance, proliferation, and metastasis. Structural studies have further characterized substrate specificity and opened avenues for designing bioorthogonal inhibitors that selectively target MAT2A activity in MTAP‐deleted tumors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in SAM biosynthesis and epigenetic regulation, MAT2A participates in broader cellular processes. It interacts with chromatin regulators to influence gene expression, modulates cellular responses under hypoxic conditions, and affects apoptotic signaling in leukemic T cells. Moreover, emerging evidence links aberrant MAT2A activity to altered methylation patterns observed in neurodegenerative conditions and congenital malformations, while its regulation by noncoding RNAs and microRNAs has been implicated in HIV-1 latency and cervical cancer progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "27"}]}, {"type": "t", "text": " Recent studies have also linked altered methionine cycle activity, mediated by MAT2A, to increased tumor aggressiveness and metastatic potential in hepatocellular carcinoma and other cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, the multilayered regulation of MAT2A—from transcriptional control and mRNA processing to post-translational modifications—underscores its central role in maintaining SAM homeostasis and modulating cellular methylation reactions. This complexity not only reflects its importance in normal physiology but also highlights MAT2A as a promising therapeutic target, with recent studies exploring inhibitors and modulators to curb its oncogenic contributions in various pathological settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Maria L Martínez-Chantar, M Ujue Latasa, Marta Varela-Rey, et al. 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