USP43 promotes gemcitabine resistance by regulating cholesterol homeostasis through E2F1 stabilization in bladder cancer

Elucidating the molecular mechanisms underlying this resistance is crucial for reversing GEM resistance. In this study, we revealed that the classical oncogene E2F1 is highly expressed in GEM-resistant cells and promotes chemoresistance.

We further demonstrated that E2F1 induces GEM resistance by transcriptionally activating NSDHL, a key enzyme in cholesterol biosynthesis, thereby increasing cholesterol production. Additionally, we characterized USP43 as the deubiquitinase responsible for stabilizing E2F1, which plays an essential role in the GEM-induced upregulation of E2F1 expression. Collectively, our findings highlight the critical role of the USP43/E2F1/NSDHL axis in cholesterol-mediated GEM resistance in BLCA, providing novel insights and therapeutic targets for overcoming chemoresistance.