SETD3 is a protein methyltransferase that primarily functions as an actin-specific histidine N-methyltransferase, catalyzing 3-methylhistidine modification at histidine 73 of actin 12. This histidine methylation contributes to cytoskeleton integrity and is required for smooth muscle contraction during uterine labor 1. The enzyme contains a catalytic SET domain for methyl transfer from S-adenosyl-L-methionine and a RuBisCO LSMT domain for substrate recognition 1. Beyond its methyltransferase activity, SETD3 plays critical roles in viral pathogenesis, particularly for enteroviruses including EV-A71 and EV-D68 3. The viral 2A protease specifically interacts with SETD3's central cleft, disrupting SETD3-actin interactions and facilitating viral RNA replication independent of SETD3's methylation activity 43. Recent evidence suggests SETD3 may also methylate other substrates, including CHD1 at lysine 209, which enhances protein stability and promotes TNF-NFκB pathway activation 5. SETD3 has been implicated in muscle hypertrophy memory through epigenetic mechanisms 6 and various cancer processes 7, indicating functions beyond its established role as an actin histidine methyltransferase 8.