HERC4 is an E3 ubiquitin ligase containing HECT and RLD domains that mediates protein ubiquitination and degradation. As an E3 ligase, HERC4 accepts ubiquitin from E2 enzymes and transfers it to target substrates 1. Physiologically, HERC4 is required for spermatozoon maturation and fertility, participating in cytoplasmic droplet removal during spermatogenesis. Mechanistically, HERC4 regulates diverse cellular processes through selective substrate targeting. In glioblastoma, HERC4 mediates polyubiquitination and degradation of DHODH at K306, with HERC4 activity suppressed by PRR11 to maintain DHODH stability and ferroptosis resistance 2. In multiple myeloma, HERC4 mediates K63-linked polyubiquitination of MafA at K33, suppressing its phosphorylation and transcriptional activity triggered by GSK3β 3. Diseases involve tissue-specific roles: HERC4 overexpression promotes hepatocellular carcinoma, breast cancer, and lung cancer progression through destabilization of tumor suppressors like LATS1 456. Conversely, HERC4 suppresses multiple myeloma proliferation 3. In immunotherapy, high HERC4 expression correlates with enhanced melanoma sensitivity to immune checkpoint inhibitors by facilitating antigen presentation 7. Clinically, HERC4 represents a therapeutic target: HERC4 knockdown suppresses cancer cell proliferation and migration, while HERC4-mediated STING degradation via compound AK59 offers potential therapeutic application for STING-related diseases 8.