USP7 (Ubiquitin Specific Peptidase 7)

Pharmacological inhibition of USP7 with FT671 and XL177A reduces KDM6A stability and viral receptor expression, and confers resistance to MERS-CoV, SARS-CoV, and all major SARS-CoV-2 variants of concern, including those resistant to remdesivir in primary human airway and intestinal epithelial cells. In mice, FT671 treatment was well tolerated, reduced Ceacam1 expression, and protected against MHV-A59 infection. Collectively, our findings unveil an antagonistic ubiquitin-mediated regulatory circuit that controls KDM6A stability, viral receptor levels, and coronavirus infection.

uncover a novel SPOP-USP7-TREX1 axis that controls cytosolic DNA clearance after DNA damage, thereby gating tumor-cell-intrinsic cyclic GMP-AMP synthase (cGAS)-STING activation and response to radioimmunotherapy. Compellingly, targeting USP7 and TREX1 might sharpen patient selection and combination strategies.

Notably, this stress response resensitizes tumors resistant to platinum-based chemotherapy. Our findings reveal a vulnerability in tumor cells that evade transcriptional shutdown and define a synthetic lethal interaction between p300 inhibition and platinum-induced DNA damage, offering a targeted strategy to overcome chemoresistance.

In conclusion, USP7 was a key regulator of DNA repair in pNENs. The combination of cisplatin and P005091 therefore holds promise as a therapeutic strategy for pNENs.

Recent studies indicate that multiple Ubiquitin-Specific Proteases (USP) family members play pivotal roles in lung cancer: Ubiquitin-Specific Peptidase 7 (USP7) promotes proliferation and osimertinib resistance in non-small cell lung cancer by stabilising proteins such as ERβ, c-Abl, and KRAS; Ubiquitin-Specific Peptidase 9, X-linked (USP9X) mediates radiotherapy resistance by regulating KDM4C and REV1; USP10 influences cellular metabolism and chemotherapy sensitivity via PTEN/AKT/mTOR and HDAC6 pathways; Ubiquitin-Specific Peptidase 14 (USP14) enhances tumour migration by regulating β-catenin and Acf7 stability; Ubiquitin-Specific Peptidase 22 (USP22) amplifies tumour stem cell properties and suppresses ferroptosis via EGFR and BMI1 signalling; Ubiquitin-Specific Peptidase 35 (USP35) and Ubiquitin-Specific Peptidase 38 (USP38) respectively modulate apoptosis resistance and proliferation through BIRC3 and KLF5; while Ubiquitin-Specific Peptidase 39 (USP39) influences mitochondrial metabolism via PDHA, thereby promoting tumour growth...It further explores the potential value of small-molecule inhibitors targeting USPs (such as P5091, IU1, and gentiopicroside) in reversing drug resistance, inducing apoptosis, and enhancing immunotherapy...This paper reviews the molecular mechanisms and targeting strategies of USPs in lung cancer based on a systematic literature search of PubMed and Web of Science databases. It further explores their potential applications in precision lung cancer therapy, providing theoretical foundations and directional guidance for future research.

To translate this mechanism, we engineered an injectable hydrogel for the sequential co-delivery of cisplatin and PRMT6/USP7 inhibitors, demonstrating significantly enhanced therapeutic efficacy. Our study unveils a previously unrecognized bifunctional role for the PRMT6-USP7 axis in orchestrating epigenetic reprogramming and DNA repair to confer platinum resistance, providing profound mechanistic insights and a compelling co-targeting strategy for overcoming chemoresistance in breast cancer.

Overexpression of MESP1 attenuated the inhibitory effects of USP7 silencing on NSCLC cell proliferation and M2 macrophage polarization and also mitigated the promoting effects of USP7 knockdown on apoptosis and the induction of features associated with ferroptosis. USP7 stabilized MESP1 to promote the malignant progression of NSCLC. The findings highlight the potential of targeting the USP7-MESP1 axis as a novel therapeutic strategy for NSCLC.

Proteomic analysis reveals that nuclear p62, unlike its cytosolic counterpart, is linked to enrichment of proteins associated with apoptosis, p53 stabilization, DNA damage response, and cellular senescence-all related to tumor suppression. These findings establish that p62 condensates provide compartment-specific regulation of ubiquitin and proteasomal degradation and suggest that manipulating their localization or affecting their dynamics can offer different therapeutic opportunities.

MBD4 downregulation significantly impaired carboplatin or etoposide efficacy in vitro and in vivo, respectively. In the present study, our findings indicate that depletion or mutation of MBD4 interferes with the activation of the cell cycle and apoptosis via epigenetic regulation, thereby reducing drug susceptibility. It provides new insights into the role in RB chemoresistance of MBD4 as an epigenetic regulator, which might fuel the development of new RB-targeted strategies.

The flexible treatment of USP7 enabled the capture of binding-site conformational changes. These changes are critical for explaining the activity differences among the studied compounds.

Furthermore, USP7 inhibitors reduce TREX1 levels and restore immune responses following radiation. These findings elucidate the mechanisms linking DNA damage to immune activation and highlight USP7 inhibitors as potential enhancers of radioimmunotherapy.

However, H3K56ac had a widespread enrichment with most BRD4-occupied sites compared with H3K27ac that occupied a limited subset of BRD4 peaks. These results present a framework of ecDNA hub chromatin organization that maintains ecDNA hub integrity, further providing therapeutic options that could be used to target ecDNA hubs.