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

作者：Wei Liu, Junlin Lu, Jiarui Li, Lu Wang, Yao Chen, Yulun Wu, Ziying Zhang, Jingying Zhang, Feng Gao, Chaoran Jia, Yongli Bao, Xiaoguang Yang, Zhenbo Song · 发表于：International Journal of Molecular Sciences · 年份：2025 · DOI：10.3390/ijms26020502 · 被引用次数：10 · 研究领域：Ferroptosis and cancer prognosis、Cancer-related molecular mechanisms research、Genomics, phytochemicals, and oxidative stress

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 protei...