UBE2L6 is a dual-function ubiquitin-conjugating enzyme that catalyzes both ISG15 conjugation (ISGylation) and ubiquitin conjugation, playing crucial roles in immune regulation and cellular processes. Under normal conditions, UBE2L6 promotes immune responses by ISGylating proteins such as STAT1, which activates STAT1 and promotes M1 macrophage polarization in obesity-related inflammation 1. However, when phosphorylated by RSK1, UBE2L6 switches its substrate specificity from ISG15 to ubiquitin, functioning with RNF19A to ubiquitinate cGAS and suppress type I interferon release, thereby promoting immune suppression and tumor resistance to checkpoint blockade therapy 2. UBE2L6 also contributes to drug resistance mechanisms, particularly in cancer chemotherapy, by regulating ABCB6 transcription to confer cisplatin resistance in ovarian cancer 3 4. Additionally, UBE2L6 promotes endothelial cell senescence in diabetic retinopathy by enhancing FoxO3a ubiquitination and degradation via p53-mediated upregulation 5. The enzyme's expression is regulated by BRCA2, as BRCA2 knockdown leads to UBE2L6 downregulation 6. These diverse functions make UBE2L6 a potential therapeutic target for immune disorders, cancer treatment resistance, and diabetic complications.