Mitocurcumin disrupts glutathione balance by modulating Klf9/GSR axis to overcome platinum resistance in non-small cell lung cancer and restores immune surveillance in cold tumor.

Chemoresistance remains a major barrier in non-small cell lung cancer (NSCLC) therapy. Glutathione reductase (GSR), a central regulator of glutathione redox homeostasis, has been implicated in tumor survival, yet its role in NSCLC chemoresistance remains unclear. We demonstrated that GSR is a critical determinant of platinum resistance in NSCLC and identified mitocurcumin (mitoC) as a promising therapeutic agent. GSR expression was elevated in platinum-resistant NSCLC cells and in relapsed patient tumors following platinum-based therapy, correlating with poor patient survival. Genetic silencing of GSR depleted intracellular glutathione, impaired proliferation, and restored chemosensitivity. Mechanistically, mitoC reversibly inhibited mitochondrial GSR activity, inducing oxidative stress and activating the Nrf2/Klf9 signaling axis, which transcriptionally repressed GSR. Notably, Klf9 depletion rescued cells from mitoC-induced ROS-dependent cytotoxicity. Resistant NSCLC cells exhibited heightened sensitivity to mitoC compared to parental or normal lung cells in vitro and in vivo. Patient-derived organoids confirmed stronger antitumor responses to mitoC in chemoresistant groups mediated through Nrf2/Klf9/GSR modulation. Moreover, mitoC suppressed growth of non-immunogenic tumors and enhanced CD8+ T cell infiltration within the tumor microenvironment. Our findings establish the Klf9/GSR axis as a novel therapeutic vulnerability in chemoresistant NSCLC and position mitoC as a strategy to overcome platinum-based treatment failure.