HERC2 is an E3 ubiquitin ligase with critical roles in DNA damage response, iron metabolism, and cancer-related pathways. Functionally, HERC2 facilitates assembly of DNA repair complexes by promoting Lys-63-linked ubiquitin chain formation at sites of DNA damage 1, and regulates the circadian oscillation of DNA excision repair through XPA degradation. HERC2 controls iron homeostasis by ubiquitinating and promoting proteasomal degradation of NCOA4 and FBXL5, thereby modulating ferritinophagy flux in an iron-dependent manner 2. This iron-regulatory function is essential for erythroid differentiation and affects cellular ferroptosis sensitivity 1. Disease relevance is significant across multiple contexts. HERC2 variants show enriched association with familial glioma (P=0.0006) 3. In hepatocellular carcinoma, elevated HERC2 expression correlates with poor prognosis and promotes cancer stemness through JAK2/STAT3 pathway activation by limiting PTP1B translocation 4. HERC2 also protects against drug-induced hepatotoxicity by limiting CYP2E1 expression through β-catenin ubiquitination 5. Additionally, HERC2 participates in orphan protein quality control through ZNRD2-mediated recognition of misassembled chaperonin subunits 6, and regulates ovarian granulosa cell senescence via NCOA4-mediated ferritinophagy 7. Clinically, HERC2 dysfunction is associated with autosomal recessive intellectual developmental disorder 38, and represents a potential therapeutic target in cancer, ferroptosis-based therapy, and tuberculosis through ferritin metabolism manipulation 8.