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 therapies. While UFL1-mediated UFMylation has been implicated in various diseases, its role in TNBC remains not fully understood. Here, we demonstrate that AKT1 directly interacts with UFL1 and undergoes UFMylation at Lys189/276/297. 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 correlates with high pAKT in TNBC specimens. These findings uncover a crucial UFL1-AKT positive feedback loop that drives TNBC progression and suggest that targeting this axis could offer a promising therapeutic strategy for TNBC and potentially other aggressive cancers characterized by upregulated UFL1 and AKT activation. The role of protein UFMylation in cancer remains to be understood. Here the authors show that UFM1-specific ligase 1 and AKT positively regulate each other through UFMylation and phosphorylation in breast cancer cells, which could be therapeutically targeted by a cell-penetrating peptide through disrupting UFL1-AKT interaction.