HECTD2 is an E3 ubiquitin ligase that plays diverse roles in cellular regulation and disease pathogenesis. The protein functions primarily through ubiquitin-mediated protein degradation, targeting specific substrates including KEAP1 in hepatocellular carcinoma cells 1 and EHMT2 in colorectal cancer 2. In hepatocellular carcinoma, HECTD2 promotes lenvatinib resistance by degrading KEAP1, thereby activating the KEAP1/NRF2 antioxidative pathway 1. In colorectal cancer, HECTD2 upregulation leads to EHMT2 degradation, which subsequently reduces H3K9me2 levels and activates pro-apoptotic genes 2. HECTD2 demonstrates significant disease relevance across multiple conditions. Genetic variants associate with prion disease susceptibility in both mice and humans, with differential expression observed in affected brain tissue 3. Rare loss-of-function variants in HECTD2 confer risk for bipolar disorder 4. In melanoma, HECTD2 drives tumor progression through cell cycle acceleration and immune evasion mechanisms, including activation of COX2 pathways 5. The protein also contributes to sepsis-induced organ damage when upregulated 6. Clinically, HECTD2 represents a potential therapeutic target, with nanoparticle-based delivery systems showing promise for overcoming drug resistance in cancer treatment 1.