Usp15, or Ubiquitin-specific protease 15, is a deubiquitinating enzyme (DUB) that plays a crucial role in the deubiquitination process, which is essential for maintaining protein stability, regulating signal pathways, and protein homeostasis [1,4,6]. It is involved in multiple biological cell processes and has been associated with pathways such as TLR signaling, RIG-I signaling, NF-κB, and IRF3/IRF7-dependent transcription, as well as p53 and TGF-β signaling [4].

In triple-negative breast cancer (TNBC), loss of ER, PR, and HER2 promotes USP15-dependent stabilization of PARP1, which stimulates DNA repair, genomic stability, and cell proliferation [2]. In gastric cancer, USP15 drives malignant progression through glucose metabolism remodeling, and its knockdown significantly impedes cell proliferation, invasion, and epithelial-mesenchymal transition [3]. In pancreatic cancer, in vivo CRISPR screens have revealed USP15 as a tumor suppressor, with loss of USP15 leading to reduced inflammatory responses and increased sensitivity to PARP inhibition and Gemcitabine [5]. In lung cancer, USP15 negatively regulates cancer progression through the TRAF6-BECN1 signaling axis for autophagy induction, and its expression is downregulated in patients [7]. In renal cell carcinoma, USP15, activated by TFAP4 transcriptionally, stabilizes SHC1 via deubiquitination and deteriorates the malignancy of the cancer [8].

In summary, Usp15 is a key deubiquitinating enzyme involved in various biological processes and disease-related pathways. Studies using in vivo models like CRISPR-based screens in pancreatic cancer and gene-editing in lung cancer cells have helped to elucidate its role in cancer progression and response to therapy. Its functions range from promoting tumorigenesis in some cancers to acting as a tumor suppressor in others, highlighting its complex and context-dependent roles in disease [2,3,5,7,8].