METTL21A is a protein-lysine methyltransferase that selectively trimethylates conserved lysine residues in heat shock protein 70 (HSP70/HSPA) family members 1. The enzyme catalyzes trimethylation of multiple HSPA proteins both in vitro and in vivo, including HSPA1, HSPA2, HSPA5, HSPA6, and HSPA8, with the reaction stimulated by ATP 1. METTL21A demonstrates remarkable specificity, exclusively methylating 70-kDa proteins in mammalian extracts. Functionally, trimethylation of HSPA8 (Hsc70) alters the chaperone's binding affinity for both monomeric and fibrillar forms of α-synuclein, suggesting involvement in protein homeostasis regulation 1. Clinically, METTL21A has emerged as relevant to multiple diseases. A rare variant in METTL21A associates with varicose veins, particularly in females 2. In hepatocellular carcinoma, METTL21A is upregulated and serves as an independent prognostic marker, with elevated expression correlating with poor prognosis 3. Conversely, in diffuse large B-cell lymphoma, high METTL21A expression associates with favorable outcome 4. METTL21A was also identified as a key gene in intracranial aneurysm pathogenesis through miRNA-mRNA network analysis 5, and appeared among hub genes in colorectal cancer molecular studies 6. These diverse disease associations suggest METTL21A may regulate critical cellular processes beyond HSP70 modification.