Targeting the METTL5-MGST1 axis for cancer therapy: molecular mechanisms and therapeutic implications.

The epitranscriptomic regulation of cancer represents one of the most rapidly expanding frontiers in oncology. Among the newly characterized epigenetic axes, the Methyltransferase-like protein 5-Microsomal Glutathione S-Transferase 1 (METTL5-MGST1) signaling axis has emerged as a mechanistically compelling circuit implicated in tumor progression, ferroptosis resistance, immune evasion, and treatment-refractory behavior, most directly established in hepatocellular carcinoma and increasingly recognized, though through varying and not always MGST1-dependent mechanisms, across other cancer types. METTL5, a ribosomal 18S rRNA N6-methyladenosine (m6A) methyltransferase stabilized by its obligate cofactor tRNA methyltransferase activator subunit 11-2 (TRMT112), orchestrates oncogenic mRNA translation by methylating adenosine 1832 (A1832) in the 18S ribosomal RNA decoding center. Among its downstream effectors, Microsomal Glutathione S-Transferase 1 (MGST1) has been identified as a key mediator of ferroptosis suppression and redox homeostasis, enabling cancer cells to resist lipid peroxidation-driven cell death and conventional therapies. This review comprehensively examines the structural biology, expression patterns, molecular mechanisms, and cancer-type-specific functions of both METTL5 and MGST1, with particular emphasis on their functional interdependence. We further discuss downstream signaling cascades including c-Myc/FBXW7, TGF-β/SMAD, Akt/GSK-3β, Nrf2/SLC7A11, and the ATF4/ferroptosis axis. The therapeutic implications of targeting this axis mainly through small-molecule inhibitors, RNA interference, CRISPR strategies, and immunotherapy combinations are critically evaluated. Understanding the METTL5-MGST1 axis provides a compelling rationale for novel combination strategies against therapy-resistant cancers.