Ubr5, also known as ubiquitin protein ligase E3 component n-recognin 5, is an E3 ubiquitin ligase belonging to the HECT family. It plays a crucial role in regulating protein degradation and various signaling pathways, participating in numerous physiological functions such as cell proliferation, autophagy, apoptosis, and cell cycle progression [4,5]. It is also involved in multiple pathophysiological processes including immune response, virus infection, DNA damage response, and protein quality control [4].

In cancer research, Ubr5-related functional studies have been extensive. In triple-negative breast cancer (TNBC), Ubr5 promotes tumor immune evasion by enhancing IFN-γ-induced PDL1 transcription in an E3 ubiquitination activity-independent manner, affecting genes in the IFN-γ-induced signaling pathway [1]. In ovarian cancer, tumor-derived Ubr5, which is overexpressed and associated with poor prognosis, promotes tumor growth and metastasis by inducing immunosuppressive macrophages and sustaining β-catenin-mediated signaling [2]. In colorectal cancer, overexpressed Ubr5 mediates chemoresistance by attenuating ferroptosis through Lys 11 ubiquitin-dependent stabilization of Smad3-SLC7A11 signaling [3]. In breast cancer, Ubr5 targets and destabilizes the tumor suppressor CDC73 by polyubiquitination, promoting aggressive breast cancer [6].

In conclusion, Ubr5 is a multifunctional E3 ubiquitin ligase involved in diverse biological processes. Its dysregulation is closely associated with cancer development, including tumor immune evasion, growth, metastasis, and chemoresistance. The study of Ubr5 in KO/CKO mouse models and other in vivo studies has provided valuable insights into its role in these disease conditions, potentially offering new therapeutic targets for cancer treatment.