Gboxin Induced Apoptosis and Ferroptosis of Cervical Cancer Cells by Promoting Autophagy-Mediated Inhibition of Nrf2 Signaling Under Low-Glucose Conditions

Cervical cancer poses a significant threat to women's health, underscoring the critical need for the development of low-toxicity, high-efficacy pharmacological drugs that specifically target cervical cancer cells. During cancer progression, elevated glucose consumption leads to a pervasive state of glucose deficiency within the tumor microenvironment (TME). Consequently, it is imperative to identify pharmacological agents capable of effectively killing cancer cells under conditions of low-glucose availability within the TME. Previous studies have demonstrated that Gboxin, a small molecular compound, effectively inhibited the growth of Glioblastoma (GBM) by targeting the activity of the ATP synthase complex, while exhibiting no detrimental effects on normal cells. However, the role and underlying molecular mechanisms of Gboxin in cervical cancer cells within a low-glucose microenvironment remain inadequately understood. This study suggested that Gboxin significantly promoted autophagy, apoptosis, and ferroptosis of cervical cells under low-glucose conditions while had no obvious effect on cell survival under normal conditons. Further study suggested that Gboxin inhibited mitochondrial function under low-glucose culture conditions while showing no significant changes on glycolysis. Mechanistic analysis revealed that Gboxin inhibited ATP synthesis and activated the AMPK signaling pathway by targeting mitochondrial complex V. Furthermore, the increased AMPK activation subsequently promoted autophagy and reduced p62 protein levels. The decreased levels of p62 protein facilitated the degradation of Nrf2 by regulating p62-Keap1-Nrf2 axis thereby diminishing the antioxidant capacity of cervical cancer cells, ultimately leading to the induction of apoptosis and ferroptosis. This study provided a better theoretical basis for exploring Gboxin as a potential drug for cervical cancer treatment.