USP25 (Ubiquitin Specific Peptidase 25)

Importantly, overexpression of USP25 increased anti-PD1 therapeutic efficacy in HNSCC in vivo. These results underscore the critical role and mechanism of USP25 in modulating the TIME in HNSCC, suggesting its potential as a therapeutic target in immune checkpoint blockade therapy.

Moreover, USP25 enhances EGFR expression through cytosolic METTL3, driving glioma progression. Our findings highlight that METTL3 undergoes distinct post-translational modifications based on its subcellular localization, providing new insights into the spatial regulation of METTL3 in gliomas.

We further show that USP25 inhibitors we have discovered are capable of destabilizing KRAS in cancer cells and are efficacious in blocking tumor xenograft growth in mice. These findings provide evidence supporting the notion that targeting the deubiquitinase USP25 can effectively, albeit indirectly, suppress KRAS and potentially aid in the treatment of tumors driven by KRAS activating mutations.

Simultaneously, targeting USP25, KIFC1 and MYCBP disrupts the malignant phenotype of CCa cells. Collectively, our findings elucidate the previously unknown functions and mechanisms of the USP25/KIFC1/MYCBP signaling axis in CCa progression, underscoring KIFC1 as a promising therapeutic target for cervical cancer.

Notably, knockin of USP25C178A in KRasG12D-driven NSCLC models fails to inhibit cancer progression and reconstitution of USP25C178A into USP25 KO A549 cells restores tumor growth. These findings identify previously uncharacterized roles of USP25 and RNF31 in oncogenic KRAS-driven NSCLC progression and provide potential therapeutic targets for KRASmuts-related cancers.

Mechanistically, Tim-3 inhibits the expression of USP25 via STAT1 and interacts with USP25 but does not regulate its posttranslational modification; as a result, Tim-3 inhibits USP25-mediated deubiquitination of TRAF3, promotes K48-linked ubiquitination and degradation of TRAF3, inhibits the phosphorylation of IRF7, and ultimately downregulates the interferon response. These findings provide new insights into the function of Tim-3 in antiviral immunity and its related clinical significance.

Notably, overexpression of long non-coding RNA eosinophil granule ontogeny transcript (EGOT) physically binds to QKI and suppressed its activity by inhibiting ubiquitin specific peptidase 25 (USP25) mediated deubiquitination and subsequent degradation of QKI. Collectively, these data demonstrate the novel mechanistic links between the splicing factor QKI and splicing event in PTC metastasis and support the potential utility of targeting splicing events as a therapeutic strategy for PTC.

Mechanistically, USP25 in macrophages promoted the activation of the ERK signaling pathway through deubiquitination and stabilization of B-Raf and C-Raf. These findings collectively suggest the critical roles of USP25 in M tuberculosis infection and its potential as a therapeutic target.

To obtain insights into their mode of inhibition, we structurally and functionally characterized USP28 in the presence of the three different inhibitors AZ1, Vismodegib and FT206...Furthermore, a key glutamate residue at position 366/373 in USP28/USP25 plays a central structural role for pocket stability and thereby for inhibition and activity. Obstructing the inhibitor-binding pocket by mutation of this glutamate may provide a tool to accelerate future drug development efforts for selective inhibitors of either USP28 or USP25 targeting distinct binding pockets.

Depletion of USP25 sensitizes colon cancer cells to IR, 5-Fu, and cisplatin...Finally, a peptide that disrupts the USP25-SHLD2 interaction is successfully identified, impairing NHEJ and increasing sensitivity to chemotherapy in PDX model. Overall, these findings reveal USP25 as a critical effector of SHLD2 in regulating the NHEJ repair pathway and suggest its potential as a therapeutic target for cancer therapy.

Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

In summary, our data showed that USP25 was overexpressed in HCC. USP25 promoted the proliferation, migration, invasion, and EMT of HCC cells by interacting with TRIM21 to activate the β-catenin signaling pathway.