SETD3, a member of SET domain-containing proteins, is the first identified metazoan actin histidine methyltransferase [1-3]. It catalyzes the Nτ -methylation of histidine 73 (His73) in actin, which is crucial for maintaining cytoskeleton integrity [1]. SETD3 is involved in multiple biological processes, such as cell differentiation, tumorigenesis, viral infection, and mitochondrial dynamics [1, 6-8].

In KO mouse models, SETD3 -deficient female mice have severely decreased litter sizes due to primary maternal dystocia, as SETD3 is essential for smooth muscle contractility in the uterus [4]. In liver carcinogenesis, SETD3 promotes in situ hepatic carcinogenesis by regulating PLK1 expression. Overexpression of SETD3 in tumor cells promotes proliferation and migration, while inhibition of PLK1 activity attenuates these phenotypes [2]. In enterovirus pathogenesis, SETD3 is critically important for viral infection. Cytosolic SETD3, independent of its methylation activity, is required for the RNA replication step in the viral life cycle, and SETD3 is essential for in vivo replication and pathogenesis in multiple mouse models for EV infection [3].

In conclusion, SETD3 plays essential roles in various biological processes, including smooth muscle contractility, tumorigenesis, and viral pathogenesis. Studies using KO mouse models have revealed its specific functions in these processes, highlighting its potential as a target for treating related diseases such as liver cancer and enterovirus -induced diseases.