Targeting the UFL1-AKT cascade suppresses triple-negative breast cancer progression

Journal article

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.

Authors: Yang, X; Wen, Y; Ma, X; Qin, S; Liu, Y

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 17
• Issue: 1
• Article number: 613
• Publication date: 2026-01-20
• Acceptance date: 2026-01-09
• DOI: 10.1038/s41467-026-68493-2
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English