The novel ferroptosis-inducing molecule can inhibit the progression of BC by regulating the ubiquitination of UHRF1.

Background: Bladder cancer remains a prevalent malignancy with limited targeted therapies. Circular RNAs have emerged as critical regulators in cancer biology, though their role in ferroptosis remains largely unexplored.

Research design and methods: The expression of circPPP6R1 was examined in BC tissues and cell lines. Functional assays, including Transwell migration, invasion, colony formation, and multiple ferroptosis-related assays, were conducted in vitro and in vivo. Mechanistic studies involved RNA pull-down, RIP, FISH, and mass spectrometry to identify circPPP6R1-interacting proteins.

Results: circPPP6R1 was significantly downregulated in BC and its overexpression inhibited BC cell proliferation, migration, and invasion. Notably, circPPP6R1 enhanced ferroptosis in BC cells. Mechanistically, circPPP6R1 directly bound to UHRF1 and facilitated its ubiquitin-mediated degradation. UHRF1 was found to be highly expressed in BC tissues and correlated with adverse clinicopathological features. Rescue experiments confirmed that the tumor-suppressive effect of circPPP6R1 was mediated through UHRF1-dependent ferroptosis induction.

Conclusions: Our study identifies circPPP6R1 as a novel ferroptosis-promoting circRNA that suppresses BC progression by targeting UHRF1. These findings highlight the circPPP6R1/UHRF1 axis as a potential therapeutic target in bladder cancer.