HERC2, short for HECT domain and RCC1-like domain 2, is an E3 ubiquitin ligase. It plays crucial roles in multiple cellular processes such as iron homeostasis, inflammation-related cancer development, and DNA repair pathways [1-3]. In iron homeostasis, it controls the levels of NCOA4 and FBXL5, which are important for regulating intracellular iron bioavailability [1,3]. In cancer, it is involved in promoting inflammation-driven cancer stemness and immune evasion in hepatocellular carcinoma by activating the STAT3 pathway [2].

In hepatocyte-specific HERC2-knockout mice, increased susceptibility to drug-induced liver injury was observed. HERC2 was found to interact with β-catenin to regulate CYP2E1 expression, and its deficiency led to more severe liver damage under APAP challenge [4]. In DEN-induced mouse liver carcinogenesis, HERC2 knockout in hepatocytes limited hepatic PD-L1 expression and ameliorated HCC progression, while its overexpression promoted tumor development in the orthotopic transplantation HCC model, highlighting its role in HCC development [2].

In conclusion, HERC2 is an important E3 ubiquitin ligase involved in iron homeostasis and cancer-related processes. Studies using gene-knockout mouse models have revealed its significance in drug-induced liver injury and hepatocellular carcinoma, providing insights into potential therapeutic targets for these disease areas.