Fig. 8: Scheme depicting the molecular mechanisms of USP9X-HIF-2ɑ proteostatic regulation in priming the HGSOC stemness downstream of hypoxic and TGF-β signaling pathway.

USP9X, as an important downstream effector, mediates TGF-β-induced stemness and chemoresistance of HGSOC via stabilizing HIF-2ɑ. Meanwhile, the hypoxia tumor microenvironment activates the TGF-β-USP9X-HIF-2α CSCs regulatory axis. WP1130, a USP9X inhibitor, represses tumor formation, and overcomes paclitaxel or platinum resistance. Antagonizing USP9X maybe a promising strategy to conquer clinical chemoresistance problem in HGSOC, even other cancers.