USP1 (Ubiquitin Specific Peptidase 1)

This RBM15-USP10-NRF2 axis drives resistance to cisplatin and 5-fluorouracil (5-FU) both in vitro and in vivo. Disruption of this pathway sensitizes GC cells to chemotherapy and suppresses tumour growth. Collectively, our findings suggest that RBM15 is both a predictive biomarker and a therapeutic target for overcoming chemotherapy resistance in GC cells.

This study uncovered a novel oncogenic axis in neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, promoting N-Myc stabilization and tumor progression. Furthermore, the findings highlight the therapeutic potential of repurposing Pimozide as a promising treatment strategy for this aggressive tumor subtype.

It further confirmed its pivotal role in CCA progression. Targeting the USP10-PRMT1-DDX1 axis may represent a significant therapeutic approach for CCA.

Finally, we discuss potential therapeutic strategies, including Proteolysis Targeting Chimeras (PROTACs), dual E3 ligase/autophagy inhibitors, and autophagy flux modulators, to overcome resistance and enhance treatment efficacy across multiple cancer types. These insights establish the foundation for targeting the ubiquitin-autophagy network as a cohesive strategy to combat refractory cancer.

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.

Targeted inhibition of YTHDC1/USP10/PLK1 axis may be an effective measure to inhibit EC progression and improve radiosensitivity.

RNA sequencing further highlighted the enrichment of cAMP, PI3K-AKT, and Wnt pathways, which are all linked to CREB activity in the combination group. These findings establish USP1 inhibition as a promising strategy to overcome Irinotecan resistance through the combination strategy, providing a novel therapeutic avenue for CRC.

Moreover, USP18 silencing promoted the accumulation of lipid reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+, thereby enhancing erastin-induced ferroptosis...Subsequent rescue experiments confirmed that the tumor-promoting effects of USP18 were abrogated upon HDAC3 knockdown. Taken together, our results identify the USP18/HDAC3 axis as a key regulator of EC cell proliferation and ferroptosis suppression, underscoring the potential of USP18 as a therapeutic target in EC.

Functional assays confirmed H10's ability to induce cell cycle arrest, senescence, and apoptosis, while proteomic analysis further highlighted its regulatory role in cell cycle regulation and ferroptosis. These findings identify calycosin H10 as a promising therapeutic candidate for ovarian cancer, offering novel insights into its molecular mechanisms of action.

This work provides mechanistic insight into the long-standing questions of how DNA viruses recruit, modulate and use cellular DDR pathways. It also puts forth CMV as a model system for further defining these pathways in human cells.

While cisplatin-based chemoradiotherapy regimens (gemcitabine-cisplatin [GP] and docetaxel-cisplatin-5-fluorouracil [TPF]) remain standard treatments for advanced nasopharyngeal carcinoma (NPC), 30-40% of patients exhibit intrinsic chemoresistance, resulting in therapeutic failure. Notably, Spautin-1, a potent USP10 inhibitor, demonstrates synergistic therapeutic activity with cisplatin in diminished tumor growth and metastasis in NPC mice. This research established the USP10-MRPS7/MRPS23-β-catenin axis as a promising precision medicine strategy to combat metastatic dissemination and reverse cisplatin chemoresistance in advanced NPC, which offers a promising opportunity to develop cisplatin sensitizers for the clinical translation of NPC therapies.

Here through CRISPR-based screens we implicate SLFN11 as the critical determinant of cisplatin sensitivity in cells lacking primase-polymerase (PrimPol)-mediated repriming...Finally, we demonstrate that rapid RPA exhaustion on chemical inhibition of DNA polymerase α activates SLFN11-dependent cell death. Together, our results implicate RPA exhaustion as a general mechanism to activate SLFN11 in response to heightened replication stress.