SETD7 is a histone lysine methyltransferase that primarily catalyzes monomethylation of histone H3 at lysine 4 (H3K4me1), a mark associated with transcriptional activation 1. Beyond its histone substrates, SETD7 methylates various non-histone proteins including p53, TAF7, PD-L1, and others, regulating their stability and activity 234. In cancer, SETD7 displays context-dependent functions, consistently preventing epithelial-to-mesenchymal transition across different tumor types while regulating cell proliferation, apoptosis, and invasion through pathways like pRb/E2F-1 1. Recent studies reveal SETD7's role in immune checkpoint regulation, where it methylates PD-L1 at K162, enhancing PD-1/PD-L1 interactions and promoting immune evasion 3. In diabetic complications, SETD7 contributes to endothelial dysfunction through a p53-FBXO45-GPX4 pathway, promoting oxidative stress and lipid peroxidation 4, while also impairing angiogenesis by transcriptionally activating the anti-angiogenic factor semaphorin-3G 5. Therapeutically, SETD7 represents a druggable target, with inhibitors like (R)-PFI-2 showing promise in rescuing diabetic vascular complications 5 and potential applications in cancer therapy based on its diverse regulatory roles 6.