{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:02:38Z","timestamp":1790928158430,"version":"4.1.0"},"reference-count":62,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Peking University Cancer Hospital","award":["312-008-10"],"award-info":[{"award-number":["312-008-10"]}]},{"award":["312-008-10"],"award-info":[{"award-number":["312-008-10"]}],"id":[{"id":"https:\/\/ror.org\/00nyxxr91","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2013Cu + FINs). Cell viability, lipid peroxidation, DLAT aggregation (cuproptosis hallmark), copper\/glutathione (GSH), mitochondrial function, and FKBP5\/Nrf2\u2013HO-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\u2013Cu 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\u2013Cu + FINs and linked to suppressed antioxidant defense (Nrf2\/HO-1). In vivo, CIN\u2013Cu + FIN treatment exacerbated fatigue-like behaviors, while TTM or hydrogen partially improved performance. FIN\u2013CIN 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.<\/jats:p>","DOI":"10.3390\/cells15151394","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T01:43:27Z","timestamp":1785721407000},"page":"1394","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Ferroptosis Inducers Combined with Copper Ionophores Aggravate Lung Cancer-Related Fatigue via GSH Depletion and FKBP5-Associated Impairment of Nrf2\/HO-1 Signaling"],"prefix":"10.3390","volume":"15","author":[{"given":"Ming","family":"Chen","sequence":"first","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education\/Beijing), Department of Psycho-Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Pang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education\/Beijing), Department of Psycho-Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education\/Beijing), Department of Psycho-Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7081-5830","authenticated-orcid":false,"given":"Yunan","family":"Ma","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education\/Beijing), Department of Laboratory Animal, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1524-4617","authenticated-orcid":false,"given":"Lili","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education\/Beijing), Department of Psycho-Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.annonc.2020.02.016","article-title":"Cancer-related fatigue: ESMO Clinical Practice Guidelines for diagnosis and treatment","volume":"31","author":"Fabi","year":"2020","journal-title":"Ann. 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