Modulation of G6PD-mediated Vitamin C Sensitivity in Small Cell Lung Cancer by the AKT/NRF2 axis.

Abstract

Small cell lung cancer (SCLC) remains a highly lethal malignancy with limited therapeutic advances. Although high-dose vitamin C (Vc) exhibits anti-tumor activity in various cancers, its therapeutic potential and underlying resistance mechanisms in SCLC remain poorly understood. Here, we identified heterogeneous responses to Vc among SCLC cell lines and found that Vc-resistant cells acquire enhanced antioxidant capacity to tolerate Vc-induced oxidative stress. Through transcriptomic, multi-omics, and functional analyses, we identified glucose-6-phosphate dehydrogenase (G6PD) as a critical determinant of Vc resistance. Mechanistically, Vc activates the p-AKT/p-GSK3β/NRF2 signaling axis in resistant cells, leading to NRF2-dependent transcriptional upregulation of G6PD and activation of antioxidant adaptation programs. Integrated analyses of transcriptomic, proteomic, single-cell, and spatial transcriptomic datasets further supported the involvement of the NRF2-G6PD axis in oxidative stress adaptation in SCLC. Importantly, pharmacological inhibition of G6PD with RRx-001 restored Vc sensitivity and synergistically suppressed SCLC growth in vitro and in vivo. Collectively, our findings reveal a previously unrecognized mechanism underlying Vc resistance in SCLC and demonstrate that co-targeting G6PD provides a potential strategy to enhance the therapeutic efficacy of Vc.

Key Findings

• Small cell lung cancer (SCLC) cells exhibit heterogeneous sensitivity to high-dose vitamin C (Vc), with resistant cells showing enhanced antioxidant capacity.
• The AKT/NRF2 signaling axis upregulates G6PD expression in Vc-resistant SCLC cells, promoting antioxidant adaptation and Vc resistance.
• Pharmacological inhibition of G6PD with RRx-001 restores Vc sensitivity and synergistically suppresses SCLC tumor growth both in vitro and in vivo.

Clinical Significance

Citation

Yao Xinhuang, Lyu Yang, Zhang Zonghuiet al.. Modulation of G6PD-mediated Vitamin C Sensitivity in Small Cell Lung Cancer by the AKT/NRF2 axis. The Journal of biological chemistry. 2026-Nov-05.