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 substantial threat to women's health, underscoring the necessity for effective therapeutic agents with low toxicity that specifically target cancer cells. As cancer progresses, increased glucose consumption causes glucose scarcity in 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 showed that Gboxin, a small molecule, inhibited glioblastoma (GBM) growth by targeting ATP synthase without harming normal cells. However, its effects and mechanisms in cervical cancer cells in low-glucose environments are not clear. This study indicates that Gboxin notably enhanced autophagy, apoptosis, and ferroptosis in cervical cells under low-glucose conditions without significantly affecting cell survival under normal conditions. Further analysis revealed that Gboxin inhibited the activity of complex V and the production of ATP, concurrently leading to a reduction in mitochondrial membrane potential and the mtDNA copy number under low-glucose culture conditions. Moreover, Gboxin inhibited tumor growth under nutrient deprivation conditions in vivo. A mechanistic analysis revealed that Gboxin activated the AMPK signaling pathway by targeting mitochondrial complex V. Furthermore, increased AMPK activation subsequently promoted autophagy and reduced p62 protein levels. The decreased levels of p62 protein facilitated the degradation of Nrf2 by regulating the p62-Keap1-Nrf2 axis, thereby diminishing the antioxidant capacity of cervical cancer cells, ultimately leading to the induction of apoptosis and ferroptosis. This study provides a better theoretical basis for exploring Gboxin as a potential drug for cervical cancer treatment.