USP9X (Ubiquitin Specific Peptidase 9 X-Linked)

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.

Furthermore, a cell-penetrating peptide mimicking the KFERQ sequence of USP9X that blocked its interaction with HSC70 and the subsequent CMA-mediated degradation, thereby promoting inflammation resolution and cardiac repair post-MI. Collectively, these findings establish the USP9X-TRAFD1 axis and its CMA-mediated degradation as critical checkpoints in post-MI inflammation, highlighting USP9X stabilization as a therapeutic strategy for ischemic heart disease.

Taken together, our findings revealed that USP9X promotes HL60/ADR cell growth in a METTL7A deubiquitination-dependent manner. Therefore, targeting USP9X or METTL7A could provide a promising therapeutic strategy to overcome ADR resistance in AML.

This review systematically summarizes the differential expression profiles of USP family members (e.g., USP1, USP3, USP7, USP8, USP9X, USP21, and USP22) in BTC and their clinical significance, with a focus on elucidating how specific USPs regulate tumor progression through key substrates, including poly(ADP-ribose) polymerase 1 (PARP1), dynamin-1-like protein (DNM1L), and O-GlcNAc transferase (OGT). Furthermore, based on recent advances, we discuss the therapeutic potential of small-molecule USP inhibitors in BTC targeted therapy, providing a theoretical foundation for developing novel precision treatment strategies.

RHOA lactylation at K118 (activation) and K162 (stabilization) orchestrated by the PCAF/HDAC3 enzymatic axis, enables constitutive oncogenic signaling to fuel tumor progression. Crucially, we redefine that lactylation at mutation-prone sites functions as a reversible "epi-mutation" system, where metabolic modification dynamically recapitulates oncogenic mutation effects, challenging the genetic/epigenetic dichotomy in oncology and revealing dual targeting of lactylation and canonical RHOA pathways as a potential therapeutic strategy.

In contrast, reduction of H3K9me3 caused partial reactivation of USP9X but not MED14, thus implicating a combinatorial action of silencing pathways in X-chromosome inactivation. Our work, in agreement with previous studies, reveals that in somatic cells XIST expression and localization suppresses the expression of escape genes.

In summary, this study revealed that NDR1 enhances the deubiquitination of AR mediated by USP9X, improving its stability and activity and thereby maintaining the continuous activation of the androgen signaling pathway in CRPC, leading to resistance to enzalutamide treatment. These findings suggest that cotargeting NDR1 and AR may represent a novel therapeutic strategy for AR-positive CRPC.

Overall, our findings established that the USP9X/WWP1 axis maintained IGF2BP2 ubiquitination homeostasis to regulate m6A-dependent oncogenic functions in TNBC. Crucially, cisplatin uniquely disrupts this balance through USP9X binding, impairing IGF2BP2's m6A recognition capacity and revealing a novel UPS-mediated drug response mechanism specific to TNBC treatment.

Targeting USP9X also enhanced the effectiveness of BRAF-targeted therapies by limiting YAP-mediated mechanosensing, drug resistance, and tumor relapse. These findings establish USP9X as a mechanoresponsive DUB essential for cancer cell adaptation to mechanical cues, proposing it as a targetable mechanosensitive therapeutic target in cancer.

Furthermore, PRICKLE3 interacted with USP9X to inhibit the DVL2 ubiquitination for the DVL2 stability and the activation of canonical WNT signaling. Overall, we demonstrate a novel signal transduction pathway where PRICKLE3 interacts with USP9X and DVL2 to enhance the DVL2 deubiquitination mediated by USP9X for stabilizing DVL2 expression and activate the canonical WNT signaling for promoting the NSCLC progression.

P1/2, N=26, Recruiting, Princess Maxima Center for Pediatric Oncology | Trial completion date: Oct 2031 --> Feb 2032 | Not yet recruiting --> Recruiting | Trial primary completion date: Oct 2031 --> Feb 2032

Also, overexpression of USP9x prevented combined treatment-induced apoptosis. These findings suggest that ZER increases TRAIL-induced apoptosis by modulating the USP9x-Mcl-1 axis and ZER may serve as a potential strategy to overcome TRAIL resistance in cancer therapy.