HERC2, also known as HECT domain and RCC1-like domain 2, is a giant E3 ubiquitin protein ligase. It is involved in multiple cellular processes such as iron homeostasis, inflammation-related cancer development, and DNA damage response. It participates in pathways like the STAT3 pathway in hepatocellular carcinoma and is associated with controlling the levels of proteins related to iron metabolism [1-3]. Genetic models, especially knockout mouse models, are valuable for studying its functions.

In hepatocyte-specific HERC2-knockout mice, hepatic PD-L1 expression was limited and HCC progression was ameliorated, indicating that HERC2 promotes inflammation-driven cancer stemness and immune evasion in HCC by activating the STAT3 pathway [1]. In liver-specific HERC2-deficient mice under APAP challenge, more severe liver damage was observed, suggesting HERC2 plays a protective role against drug-induced liver injury by regulating β-catenin-regulated CYP2E1 expression [2].

In conclusion, HERC2 is essential in regulating various biological processes and is involved in multiple disease conditions, including hepatocellular carcinoma and drug-induced liver injury. The use of HERC2 knockout mouse models has significantly contributed to understanding its role in these disease areas, highlighting its potential as a therapeutic target.