USP5 (Ubiquitin Specific Peptidase 5)

While USP5 inhibitor WP1130 downregulated ILF2 and inhibited CRC cell growth, the effects were markedly abolished by ILF2 overexpression. These data demonstrate that the USP5/ILF2 axis mediates the tumorigenesis of CRC, which highlights the USP5/ILF2 axis as a promising therapeutic target for CRC treatment.

Notably, USP5 stabilizes C2CD5 through deubiquitination, thereby activating the phosphoinositide 3-kinase (PI3K)/ (protein kinase B) AKT/ mechanistic target of rapamycin (mTOR) signaling pathway and enhancing glycolytic flux via the HIF-1α transcription factor to drive AML progression. Importantly, USP5 knockdown enhanced the chemosensitivity of AML cells, and its small-molecule inhibitor potently curbed AML cell growth and proliferation. Generally, our findings establish the USP5-C2CD5 as a novel therapeutic target for AML treatment.

This process promotes the expression of T cell chemokines and upregulates the antigen presentation machinery, thereby enhancing radiation-induced CD8+ T cell antitumor immunity and radiotherapy efficacy. Our findings reveal a critical role of USP5 in type I IFN-induced antitumor immunity, providing potential targets for improving the efficacy of radiotherapy.

Notably, the positive correlation between USP5 and FASN expression in HCC tissues was observed, and USP5 exerted oncogenic effects partly via FASN. Our findings revealed that USP5 promotes HCC progression through deubiquitinating FASN, and targeting the USP5-FASN-PA axis could potentially serve as a strategic approach for the therapy of HCC.

In addition, we showed that USP5 serves as an oncogene in CRC by deubiquitinating STAT3, which contributes to CRC progression. Overall, our study provided evidence that α-hederin exhibits significant potential in suppressing colorectal tumorigenesis by disrupting USP5-mediated STAT3 deubiquitination.

Systematic functional assays and mechanistic studies further confirmed that the USP5/YBX3/SLC7A11 axis is a central pathway for ferroptosis resistance in CRC. These findings provide novel insights into therapeutic strategies for CRC, especially ferroptosis-based treatments.

USP5 appears to be a reliable marker for diagnosing NSCLC and predicting its prognosis. Further investigation into the role of USP5 in immune responses may aid in the development of immunotherapies for NSCLC.

Furthermore, knockdown of FASN inhibited the palmitoylation of USP5, reducing its interaction with GPX4 and consequently increasing GPX4 ubiquitination and degradation. Our results demonstrate that FASN suppresses ferroptosis in BC by stabilizing GPX4 via USP5-mediated mechanisms, highlighting FASN inhibition as a potential therapeutic approach to enhance immunotherapy response.

Deubiquitinating enzyme family protein USP5 upregulation and stability of apoptotic protein SMAC are found important indicator in balancing the TRAIL resistance glioma to opt unidirectional pathway which is not aberrant but rewired on W. somnifera FE treatment. Therefore, knockdown of USP5 make cells sensitive to undergo direct apoptosis.

Its inhibition sensitizes glioma cells to TRAIL-induced apoptosis, identifying SETD5 as a potential therapeutic target. Targeting SETD5 could represent a novel strategy to overcome TRAIL resistance and enhance the efficacy of GBM therapies.

In addition, in a patient-derived xenograft (PDX) model, this compound, when combined with 5-azacytidine (5-Aza), improved therapeutic effects. This study presents promising targeted therapeutic possibilities for the treatment of t(8;21) AML that require further study.