Inhibition of Endoplasmic Reticulum Stress Cooperates with SLC7A11 to Promote Disulfidptosis and Suppress Tumor Growth upon Glucose Limitation.

Abstract

Disulfidptosis is a newly discovered type of regulated cell death triggered by disulfide bond accumulation and NADPH (nicotinamide adenine dinucleotide phosphate) depletion due to glucose deprivation. However, the regulatory mechanisms involving additional cellular circuits remain unclear. Excessive disulfide bond accumulation can impair endoplasmic reticulum (ER) homeostasis and activate the ER stress response. In this study, we found that SLC7A11-mediated disulfidptosis upon glucose deprivation is accompanied by ER stress induction. Pharmacological inhibition of SLC7A11-mediated cystine uptake or cystine withdrawal not only blocks disulfidptosis under glucose starvation but also suppresses the ER stress response, indicating a close link between these processes. Moreover, inhibitors targeting the ER stress response promote disulfidptosis, while ER stress inducers suppress glucose starvation-induced disulfidptosis in SLC7A11-high-expressing cells, suggesting a protective role for ER stress during disulfidptosis. Similar effects are observed in cells treated with glucose transporter inhibitors (GLUTi). Finally, combined treatment with ER stress inhibitors and GLUTi significantly suppresses tumor growth both in vitro and in vivo by inducing disulfide stress and subsequent disulfidptosis. In summary, these findings reveal a novel role for ER stress in regulating disulfidptosis and provide theoretical insights into the potential application of GLUTi and ER stress inhibitors in cancer therapy.