Ferroptosis Inducers Combined with Copper Ionophores Aggravate Lung Cancer-Related Fatigue via GSH Depletion and FKBP5-Associated Impairment of Nrf2/HO-1 Signaling

Cancer-related fatigue (CRF) remains difficult to manage, and the impact of metal ion-regulated cell death on peripheral fatigue during anticancer therapy is unclear. Here, we investigated whether ferroptosis inducers (FINs) potentiate copper ionophore (CIN)-triggered cuproptosis in skeletal muscle and aggravate lung cancer-related fatigue (LCaRF), and evaluated redox-based interventions. LCaRF cellular models were established using C2C12 exposed to LLC/M109 tumor-conditioned supernatants and treated with FINs (sorafenib/erastin) plus CIN + CuCl2 (CIN–Cu + FINs). Cell viability, lipid peroxidation, DLAT aggregation (cuproptosis hallmark), copper/glutathione (GSH), mitochondrial function, and FKBP5/Nrf2–HO-1 signaling were assessed with pharmacologic and genetic modulation. An orthotopic lung cancer mouse model underwent wheel-running, tail suspension, and open-field testing with tetrathiomolybdate (TTM) or hydrogen as interventions. FINs sensitized C2C12 cells to CIN–Cu cytotoxicity and increased DLAT aggregation; copper chelation with TTM attenuated these effects. FINs depleted GSH and amplified mitochondrial dysfunction/ROS; exogenous GSH or hydrogen reduced DLAT aggregation and restored mitochondrial indices. FKBP5 was markedly upregulated by CIN–Cu + FINs and linked to suppressed antioxidant defense (Nrf2/HO-1). In vivo, CIN–Cu + FIN treatment exacerbated fatigue-like behaviors, while TTM or hydrogen partially improved performance. FIN–CIN combinations may aggravate skeletal muscle injury and fatigue-like phenotypes in LCaRF models by promoting cuproptosis via GSH depletion and FKBP5/Nrf2-HO-1 dysregulation.