Glutathione-Driven Redox Inducer with Disruption of the SLC7A11/GSH/GPX4 Axis for Enhanced Ferroptotic Therapy

Abstract Non-small-cell lung cancer (NSCLC) is a lethal malignant tumor worldwide. Although ferroptosis offers a promising route for curcumin-mediated non-small-cell lung cancer therapy, its efficacy is often constrained by the robust antioxidant defense maintained by the SLC7A11/GSH/GPX4 axis, which continuously sustains cystine uptake, glutathione biosynthesis, and GPX4-dependent lipid peroxide detoxification, thereby maintaining cellular homeostasis. Herein, we developed a glutathione-responsive metal–organic framework nanoplatform for the co-delivery of curcumin and a GPX4-targeting antisense oligonucleotide (ASO). After cellular internalization, the disulfide-bearing framework underwent GSH-triggered disassembly, enabling synchronized release of curcumin and ASO while depleting the intracellular GSH. Released curcumin increased ROS accumulation and disturbed redox homeostasis, whereas ASO silenced GPX4 expression to concurrently disable the antioxidant defense. Flow cytometry and Western blot assays confirmed significant ROS accumulation and SLC7A11 downregulation, which were detailed by molecular dynamics simulations with putative binding modes. Furthermore, the nanocomposite demonstrated robust anticancer effects in 3D multicellular tumor spheroids with a promoted oxidative imbalance. Taken together, this coordinated intervention disrupted the SLC7A11/GSH/GPX4 antioxidant axis, amplified lipid peroxidation, impaired mitochondrial function, and ultimately enhanced ferroptotic vulnerability.