KMT5C is a histone methyltransferase that catalyzes di- and trimethylation of histone H4 lysine 20 (H4K20me2/3), playing critical roles in DNA repair, heterochromatin formation, and transcriptional regulation 1. The enzyme promotes DNA repair by interacting with RAD51 and facilitating homologous recombination repair complex formation, which depends on its methyltransferase activity 1. KMT5C also exhibits non-catalytic functions, including regulation of hepatic gluconeogenesis by preventing PGC-1α degradation through inhibition of E3 ligase RNF34 binding 2. In cancer contexts, KMT5C is significantly overexpressed and promotes tumor progression across multiple cancer types including hepatocellular carcinoma, non-small cell lung cancer, and clear cell renal cell carcinoma 134. The protein facilitates immune evasion by activating DNA repair responses that inhibit the STING-IRF3 pathway and reduce CD8+ T cell infiltration 3. Clinically, high KMT5C expression correlates with poor patient prognosis and reduced response to immunotherapy 3. KMT5C represents a promising therapeutic target, as both genetic and pharmacological inhibition (using inhibitor A196) sensitize cancer cells to PARP inhibitors and enhance immunotherapy efficacy 13.