Abstract

Highlights What are the main findings? Ferroptosis inducers (FINs) sensitize skeletal muscle cells to copper ionophore (CIN)–Cu stress, enhancing cuproptosis hallmarks such as DLAT aggregation, mitochondrial dysfunction, ROS accumulation, and cytotoxicity. FINs deplete intracellular glutathione (GSH) and induce FKBP5 upregulation, which is associated with impaired Nrf2/HO-1 antioxidant signaling and increased vulnerability to cuproptosis. What are the implications of the main findings? Copper chelation with tetrathiomolybdate (TTM) counteracts FIN–CIN–Cu synergy, supporting a copper-dependent mechanism underlying aggravated skeletal muscle injury. In an orthotopic lung cancer mouse model, CIN–Cu + FINs worsen fatigue-like behaviors, whereas TTM or molecular hydrogen partially improves performance, suggesting potential supportive intervention strategies. 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 + CuCl 2 (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 m