Usp9x-flox Mouse

Usp9x, or ubiquitin-specific peptidase 9 X-linked, is a deubiquitinase that plays a crucial role in various biological processes. It promotes the deubiquitination and stabilization of diverse substrates, thereby influencing multiple physiological and pathological pathways [4].

In macrophages, disruption of Usp9x promotes foam cell formation and atherosclerosis. Macrophage Usp9x-deficient mice showed increased macrophage infiltration, lipid deposition, and necrotic core content in atherosclerotic lesions compared to control Apoe-/-mice. Mechanistically, Usp9x removes the K63 polyubiquitin chain of SR-A1 at the K27 site, and inhibition of Usp9x increases SR-A1 cell-surface internalization after ox-LDL binding [1].

In glioblastoma stem cells, depletion of Usp9x downregulates ALDH1A3, resulting in loss of self-renewal and tumorigenic capacity. The USP9X inhibitor WP1130 shows efficacy in MES GSC-derived orthotopic xenograft models [2].

In lung cancer, depletion of Usp9X impairs TGF-β2/Smad signaling and radioresistance by destabilizing KDM4C [3].

In laryngeal cancer, knockdown of Usp9X led to decreased proliferation, migration, and invasion of FaDu cells, and increased apoptosis [6].

In liver fibrosis, USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells [5].

In P301S mice, inhibition of USP9X with WP1130 promoted autophagy and accelerated tau degradation, highlighting it as a potential target for tauopathies [7].

In sepsis-induced acute kidney injury, interference with Usp9x alleviated the inflammatory response and apoptosis of renal tubular epithelial cells [8].

In conclusion, Usp9x is a key deubiquitinase involved in multiple biological processes and diseases. Gene knockout or conditional knockout mouse models, such as macrophage Usp9x-deficient mice, have been instrumental in revealing its role in atherosclerosis, cancer development, fibrosis, neurodegenerative diseases, and kidney injury. These findings provide potential therapeutic targets for these disease areas.