Targeting the UFL1-AKT Cascade Suppresses Triple-Negative Breast Cancer Progression

Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease with limited therapeutic options. While UFL1-mediated UFMylation has been implicated in various diseases, its role in TNBC remains unexplored. In this study, we demonstrate that AKT1 directly interacts with UFL1 and undergoes UFMylation at Lys189, Lys276, and Lys297. This modification enhances AKT phosphorylation and activation, promoting tumor growth and chemoresistance in TNBC. In turn, AKT phosphorylates UFL1 at Thr426, establishing a positive feedback loop that sustains high activity of both pro-oncogenic regulators in TNBC. Disrupting the UFL1-AKT interaction using the specific peptide PDAU-TAT significantly inhibits TNBC progression both in vitro and in vivo. Clinically, elevated pT426 UFL1 expression significantly correlates with increased pAKT levels in TNBC specimens. These findings uncover a crucial positive feedback loop between UFL1 and AKT that drives TNBC progression and suggest that targeting the UFL1-AKT axis could offer a promising therapeutic strategy for TNBC and potentially other aggressive cancers characterized by upregulated UFL1 and AKT activation.