Nedd4, also known as NEDD4-1, is an E3 ubiquitin ligase. E3 ubiquitin ligases catalyze the covalent binding of ubiquitin to protein substrates, determining substrate specificity in the ubiquitination process, which is a crucial post-translational modification involved in various cellular functions [2,4,5,6,7,8]. Ubiquitination can lead to protein degradation, and Nedd4 is implicated in multiple biological pathways, influencing processes such as cell proliferation, apoptosis, and drug resistance [2,4,7]. Genetic models, like knockout mouse models, are valuable for studying Nedd4's functions.

In melanoma, Nedd4 is induced by erastin treatment. It ubiquitinates VDAC2/3, leading to their degradation and suppressing erastin-induced ferroptosis. Depletion of Nedd4 limits VDAC2/3 degradation, increasing cancer cells' sensitivity to erastin [1]. In acetaminophen-induced liver injury, hepatocyte-specific NEDD4-1 knockout exacerbates mitochondrial damage, hepatocyte necrosis, and liver injury, while overexpression mitigates these events. NEDD4-1 interacts with VDAC1 and regulates its K48-linked ubiquitination and degradation [3].

In conclusion, Nedd4, as an E3 ubiquitin ligase, plays essential roles in multiple biological processes through regulating the degradation of various substrates. The study of Nedd4 using knockout mouse models has revealed its significance in diseases such as melanoma and acetaminophen-induced liver injury, providing insights into disease mechanisms and potential therapeutic targets.