SMYD3 was a crucial factor in regulating SCLC sensitivity to alkylation-based chemotherapy. This PMT methylated RNF113A, which interfered with its ability to interact with the protein phosphatase 4 (PP4), and consequently affecting RNF113A’s phosphorylation levels. The interplay between these PTMs (methylation and phosphorylation) served as a critical mechanism for activating and maintaining RNF113A’s E3 ligase activity. This activity was essential for RNF113A’s role in responding to alkylation-induced DNA damage. Inhibiting SMYD3 restored SCLC’s vulnerability to alkylating chemotherapy. The gene discussed is RNF113A; the disease is small cell lung carcinoma.