USP18 (Ubiquitin Specific Peptidase 18)

Background/Objectives: Carfilzomib (CFZ) and bortezomib (BTZ) are proteasome inhibitors used as the first-line therapy for relapsed or refractory multiple myeloma (MM) but are associated with cardiovascular adverse events (CVAEs). Pathway enrichment analyses identified peroxisome, MAPK, Rap1, adherens junction, phospholipase D, autophagy, and aldosterone-related pathways to be implicated in CVAEs. Our study identified distinct DMPs, DMRs, and pathways enrichment associated with CVAE, suggesting epigenetic contributors to CVAEs and supporting the need for larger validation studies.

This study unveils a previously unrecognized oncogenic mechanism wherein USP18 promotes malignant progression of nasopharyngeal carcinoma via UBR5-dependent suppression of the p53 signaling pathway. These findings highlight USP18 as a promising candidate biomarker and potential therapeutic target in NPC.

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.

USP18 directly bound and stabilized NBR1 by deubiquitinating it, thereby inhibiting its proteasomal degradation. Collectively, our findings unveil the USP18-NBR1-MHC-I axis as a central mechanism driving immune evasion in PDAC and highlight USP18 as a promising therapeutic target for overcoming resistance to immunotherapy.

Clinically, high USP18 levels are associated with worse patient prognosis. Our findings underscore the critical role of USP18 in modulating DDR signaling and radiosensitivity in NPC, suggesting that targeting the USP18-TRIM21-TRIM29 axis may represent a novel strategy to enhance the efficacy of radiotherapy for patients with NPC.

These biomarkers may enhance early diagnosis, enable personalized therapy, and improve kidney disease outcomes. Their integration into clinical practice may bridge the gap between early detection and effective intervention, potentially improving long-term outcomes in patients with kidney disease.

Treatment with IFN-α (+/- 5-fluorouracil (5-FU) or oxaliplatin) induces ISGylation network proteins, including USP18. USP18 depletion also elevated LC3 II expression and autophagosome formation induced by IFN-α (+/- chemotherapeutic agents), indicative of autophagy. These findings demonstrate that strategies to inhibit USP18 could re-engage cell death signalling and restore sensitivity to chemo-resistant oesophageal cancer cells.

Both of which selectively decrease the viability and alter the morphologies of organoids of h SKP2 knock-in rather than wild-type mice. Our studies provide a well-characterized prostate-specific h SKP2 knock-in mouse model and offer new mechanistic insights for understanding the oncogenic role of SKP2 in shaping the prostatic microenvironment during early carcinogenesis.

Importantly, we screened and identified hyperoside (HYP) as a new USP18 enzyme activity inhibitor, which sensitizes cancer cells to existing targeted therapies (sorafenib and regorafenib) by inhibiting USP18 and following deISGylation of NCOA4. Collectively, our study has uncovered a novel mechanism of acquired sorafenib resistance and offers a promising combination therapy strategy for overcoming therapeutic resistance in HCC.

Additionally, we identified YY1 as a transcriptional regulator of USP18, increasing its expression in GBM cells. These findings reveal that USP18 is a potential therapeutic target and highlight the novel YY1/USP18/SOX9 signalling axis implicated in GBM progression.

Based on comprehensive bioinformatic analysis, MACC1 was identified as the most promising MRG candidate in EC. Systematic experimental validation, including both in vitro and in vivo approaches, demonstrated that MACC1 down-regulation significantly suppressed EC progression, highlighting its potential as a therapeutic target.