Targeting PRDX1-G6PD Interaction Promotes a Metabolic Vulnerability and Redox Imbalance in Triple-Negative Breast Cancer.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited targeted options, and its progression is strongly driven by metabolic reprogramming and redox homeostasis. Here, we found that peroxiredoxin-1 (PRDX1) promotes TNBC progression by directly interacting with glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP). Mechanistically, PRDX1 depletion reduced the formation of active G6PD dimers without affecting its expression, thereby impairing PPP metabolism and ultimately suppressing TNBC growth. Furthermore, we identified the natural product Oridonin as a small-molecule disruptor that blocked the PRDX1-G6PD interaction. Pharmacological intervention with Oridonin impaired G6PD dimerization, disrupted intracellular redox homeostasis and suppressed TNBC tumor growth in vivo. Taken together, our study unveils the critical role of the PRDX1-G6PD protein complex in PPP-dependent metabolic reprogramming and redox homeostasis in TNBC, and identifies this axis as a targetable vulnerability against TNBC.