UCHL5 (Ubiquitin C-Terminal Hydrolase L5)

DK-7, a quinoxaline-based UCHL5 inhibitor, selectively triggers ER stress and apoptosis, effectively overcomes bortezomib resistance, and exhibits antitumor activity in solid tumors. These findings highlight UCHL5 as a promising therapeutic target and suggest quinoxaline-based DUB inhibitors as a next-generation proteasome-targeted strategy with broad clinical potential.

Conversely, LY294002 inhibited the glycolytic enhancement and aggressive phenotypes induced by UCHL5 overexpression (P < 0.01)...UCHL5 activates the PI3K/AKT/mTOR cascade, which enhances the glycolysis of RCC cells and promotes the development of renal cancer. This study provides insights into the molecular mechanisms underlying the oncogenic role of UCHL5 in RCC.

Our findings demonstrated that the TMEM158-TGF-β pathway plays a central role in mediating the heightened sensitivity of TP53-deficient OS to USP14 inhibition. Targeting this pathway may represent a promising therapeutic strategy for precision treatment of osteosarcoma.

In vivo, bAP15 suppressed xenograft growth. Collectively, these data support proteasome-associated DUB inhibition as a potential strategy in chondrosarcoma, with bAP15 serving as a chemical tool to probe this target class.

COL17A1, a collagen highly and specifically expressed in HNSCC, mediates in part Uchl5-mediated immune evasion. Our findings suggest an unappreciated role for UCHL5 in promoting EMT in HNSCC and highlight ECM modulation as a strategy to improve immunotherapy responses.

Expression of this Ub chain debranching-specific nanobody in cells enabled identification of proteins whose degradation depends on UCH37. This work provides novel tools for investigating the biological functions of UCH37 and lays the groundwork for evaluating its potential as a therapeutic target.

Mechanistically, USP14 and UCHL5 cooperate to stabilize PKCα by concurrently removing K48-linked ubiquitination chains from PKCα, thereby facilitating the nuclear translocation of transcription factor NF-κB and activating the expression of pro-oncogenic and anti-apoptotic genes, such as C-MYC and BCL-XL. These findings suggest that targeting the USP14/UCHL5-PKCα-NF-κB axis may represent a novel therapeutic approach for ATC, offering promising prospects for the development of innovative treatment strategies against this highly lethal disease.

These data provide additional insights into the functional characteristics of proteasome-low/ALDH-high CSCs, indicating a metabolic phenotype of reduced reliance on aerobic glycolysis and a decreased protein synthesis rate. We also identify specific chaperone and ubiquitin ligase activities that can be used to identify CSCs, with corresponding implications for therapeutic strategies that target CSCs through their altered metabolic properties.

Molecular docking into the active site of CCHFV OTU proposes starting points for further structural modifications to improve activity and selectivity. These structure-activity relationships are the first to our knowledge to be reported for the CCHFV OTU protease and will help guide further drug discovery efforts.

Pan-cancer analysis indicates that UCHL5 is dysregulated in various tumor tissues and is closely associated with survival prognosis, the tumor immune microenvironment, and the efficacy of immunotherapy in certain cancer types. UCHL5 shows promise as a predictive biomarker, and its specific regulatory mechanisms across different cancers warrant further investigation.

Furthermore, the overexpression of B-cell lymphoma-extra-large and myeloid cell leukemia-1 prevented the cell death caused by b-AP15 and AUR. These results suggest that inhibiting USP14/UCHL5, which involves multiple regulatory mechanisms, is a promising target for novel therapies for treatment-resistant FLT3-ITD-positive AML.

Both the two pathways are involved in the regulation of FASN in liver cancer. Our results reveal a novel mechanism for FASN accumulation due to the low expression of SIAH1 in human liver cancer and suggest an important role of FASN in filopodia formation in liver cancer cells.