The Role of Glucose-6-Phosphate Dehydrogenase in Breast Cancer Metastasis: Insights into G6PD Inhibition as a Therapeutic Strategy

Abstract

Breast cancer is the most commonly diagnosed cancer in women worldwide, with metastasis accounting for the majority of breast cancer-related deaths. During metastatic progression, tumour cells encounter substantial oxidative and metabolic stress, requiring adaptive mechanisms to support survival. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, plays a central role in maintaining redox homeostasis through NADPH production. This study investigated the role of G6PD in breast cancer stress adaptation using both pharmacological inhibition with G6PDi-1 and doxycycline-inducible knockdown models. Pharmacologic G6PD inhibition reduced breast cancer cell viability under nutrient stress conditions, increased reactive oxygen species levels, enhanced sensitivity to doxorubicin, and altered anchorage-independent growth. Collectively, these findings suggested that G6PD may contribute to breast cancer cell survival under oxidative and metabolic stress and targeting G6PD could represent a promising therapeutic strategy, either alone or in combination with conventional chemotherapies, for the treatment of metastatic breast cancer.