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

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. 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. 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. 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. Bladder cancer is a common type of cancer that currently has limited treatment options. In recent years, scientists have discovered that a group of molecules called circular RNAs may play important roles in how cancers grow and spread. In this study, we focused on a circular RNA called circPPP6R1, which was found at lower levels in bladder cancer tissues compared to normal tissues. When we increased the amount of this RNA in cancer cells, the cells grew and spread less, and they were more likely to die through a specific type of cell death called ferroptosis. We also discovered that circPPP6R1 works by attaching to a protein called UHRF1, which is often found in high amounts in bladder cancer and is linked to worse outcomes. circPPP6R1 helps break down this protein, which in turn makes the cancer cells more sensitive to ferroptosis. These findings suggest that circPPP6R1 May be a helpful target for future treatments and could lead to new ways to slow down or stop bladder cancer.