{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:31:36Z","timestamp":1787027496521,"version":"build-2736575974"},"reference-count":33,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81973236"],"award-info":[{"award-number":["81973236"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82104246"],"award-info":[{"award-number":["82104246"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["81973236"],"award-info":[{"award-number":["81973236"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82104246"],"award-info":[{"award-number":["82104246"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007128","name":"Natural Science Foundation of Shaanxi Province","doi-asserted-by":"crossref","award":["2025JC-YBMS-917"],"award-info":[{"award-number":["2025JC-YBMS-917"]}],"id":[{"id":"10.13039\/501100007128","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100007547","name":"Fourth Military Medical University","doi-asserted-by":"crossref","award":["2024JC054"],"award-info":[{"award-number":["2024JC054"]}],"id":[{"id":"10.13039\/501100007547","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2024JC054"],"award-info":[{"award-number":["2024JC054"]}],"id":[{"id":"https:\/\/ror.org\/00ms48f15","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Radiation-induced liver injury (RILI) is a major complication of abdominal radiotherapy, originating from mitochondrial oxidative stress, and effective radioprotectants are lacking. We designed an antioxidant intended to target mitochondria, TPP-C6-NIT, by conjugating a triphenylphosphonium cation to an imidazole nitroxide radical. Its protective effects were evaluated through in vitro assays, studies on irradiated L-02 and Huh-7 cells, a mouse model of whole-body irradiation, combined with metabolomics, molecular docking, and assessments of mitochondrial function, apoptosis, and inflammation. TPP-C6-NIT exhibited potent radical scavenging activity in vitro. In L-02 cells, it reduced oxidative stress, preserved mitochondrial function (membrane potential, ATP, respiratory capacity), and improved viability. In mice, pretreatment with TPP-C6-NIT significantly improved survival, alleviated liver injury (reduced serum ALT\/AST and histopathological damage), and suppressed systemic inflammation. Mechanistic exploration suggested TPP-C6-NIT treatment was associated with increased Nrf2\/GPX4 expression and reversal of lipid metabolic changes. Notably, TPP-C6-NIT did not confer significant protection in Huh-7 cells, indicating selective cytoprotection. By reducing oxidative stress and preserving mitochondrial function, TPP-C6-NIT demonstrates potent protection against radiation-induced liver injury in a whole-body irradiation mouse model, presenting a promising candidate for further development.<\/jats:p>","DOI":"10.3390\/antiox15060780","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:52:11Z","timestamp":1782453131000},"page":"780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Mitochondria-Targeted Nitroxide Radical Mitigates Radiation-Induced Liver Injury by Attenuating Oxidative Stress and Preserving Mitochondrial Function"],"prefix":"10.3390","volume":"15","author":[{"given":"Miaomiao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Chemistry, School of Pharmacy, The Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"Department of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Pharmacy, The Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Pharmacy, The Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e545","DOI":"10.1016\/S1470-2045(24)00407-8","article-title":"Radiotherapy and theranostics: A Lancet Oncology Commission","volume":"25","author":"Giammarile","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.semradonc.2018.06.007","article-title":"Radiation-induced liver disease and modern radiotherapy","volume":"28","author":"Koay","year":"2018","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1080\/15384101.2022.2131163","article-title":"Radiation-induced liver disease: Beyond DNA damage","volume":"22","author":"Zhou","year":"2023","journal-title":"Cell Cycle"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"ii91","DOI":"10.1093\/jrr\/rrx091","article-title":"Potential relationship between the biological effects of low-dose irradiation and mitochondrial ROS production","volume":"59","author":"Kawamura","year":"2018","journal-title":"J. Radiat. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Liu, Y., Xu, Y., Ji, H., Gao, F., Ge, R., Zhou, D., Fu, H., Liu, X., and Ma, S. (2024). AdipoRon Alleviates Liver Injury by Protecting Hepatocytes from Mitochondrial Damage Caused by Ionizing Radiation. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252011277"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7618","DOI":"10.1038\/s41598-025-91331-2","article-title":"Enhancing radiation-induced reactive oxygen species generation through mitochondrial transplantation in human glioblastoma","volume":"15","author":"Marshall","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5383","DOI":"10.1021\/acs.molpharmaceut.3c00600","article-title":"Advances of Amifostine in Radiation Protection: Administration and Delivery","volume":"20","author":"Ji","year":"2023","journal-title":"Mol. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15203","DOI":"10.1021\/acsami.3c00502","article-title":"Amifostine-Loaded Nanocarrier Traverses the Blood-Brain Barrier and Prevents Radiation-Induced Brain Injury","volume":"15","author":"Zhao","year":"2023","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3679","DOI":"10.1021\/jp056869r","article-title":"Structure-Activity Relationship of Cyclic Nitroxides as SOD Mimics and Scavengers of Nitrogen Dioxide and Carbonate Radicals","volume":"110","author":"Goldstein","year":"2006","journal-title":"J. Phys. Chem. A"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1016\/j.freeradbiomed.2007.02.030","article-title":"The chemistry and biology of nitroxide compounds","volume":"42","author":"Soule","year":"2007","journal-title":"Free Radic. Biol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1186\/s12943-024-02142-4","article-title":"Anti irradiation nanoparticles shelter immune organ from radio-damage via preventing the IKK\/I\u03baB\/NF-\u03baB activation","volume":"23","author":"Huang","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41413-025-00460-x","article-title":"The impact of mitochondrial dysfunction on osteoarthritis cartilage: Current insights and emerging mitochondria-targeted therapies","volume":"13","author":"Tan","year":"2025","journal-title":"Bone Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.freeradbiomed.2025.07.017","article-title":"MitoQ alleviates prion-induced neurodegeneration by modulating DRP1- and OPA1-mediated mitochondrial dynamics","volume":"238","author":"Wu","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2579","DOI":"10.1021\/acsami.8b00949","article-title":"Graphdiyne Nanoparticles with High Free Radical Scavenging Activity for Radiation Protection","volume":"11","author":"Xie","year":"2019","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"116481","DOI":"10.1016\/j.lfs.2019.05.037","article-title":"Protective effects of two novel nitronyl nitroxide radicals on heart failure induced by hypobaric hypoxia","volume":"248","author":"Jing","year":"2020","journal-title":"Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"112847","DOI":"10.1016\/j.biopha.2022.112847","article-title":"The enhanced mitochondrial dysfunction by cantleyoside confines inflammatory response and promotes apoptosis of human HFLS-RA cell line via AMPK\/Sirt 1\/NF-\u03baB pathway activation","volume":"149","author":"Bai","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"23191","DOI":"10.1038\/s41598-025-04845-0","article-title":"Ionizing radiation triggers the release of mitochondrial DNA into the cytosol as a signal of mitochondrial damage","volume":"15","author":"Shimura","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"jcs263459","DOI":"10.1242\/jcs.263459","article-title":"Fis1 regulates mitochondrial morphology, bioenergetics and removal of mitochondrial DNA damage in irradiated glioblastoma cells","volume":"138","author":"Buckley","year":"2025","journal-title":"J. Cell Sci."},{"key":"ref_19","first-page":"100","article-title":"Dynamic Metabolomics Atlas of Radiation-induced Liver Injury and Hepatocyte Proliferation Process in Rat","volume":"205","author":"Wu","year":"2026","journal-title":"Radiat. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Greenberger, J.S., Clump, D., Kagan, V., Bayir, H., Lazo, J.S., Wipf, P., Li, S., Gao, X., and Epperly, M.W. (2011). Strategies for Discovery of Small Molecule Radiation Protectors and Radiation Mitigators. Front. Oncol., 1.","DOI":"10.3389\/fonc.2011.00059"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1186\/s12964-025-02160-9","article-title":"Atovaquone-induced activation of the PERK\/eIF2\u03b1 signaling axis mitigates metabolic radiosensitisation","volume":"23","author":"Feng","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5007","DOI":"10.1021\/acs.molpharmaceut.5c00671","article-title":"Engineering Magnesium Oxide as a Mitochondrial Electron Transport Chain Inhibitor for Enhanced Photodynamic Therapy in Triple-Negative Breast Cancer","volume":"22","author":"Zhang","year":"2025","journal-title":"Mol. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"23140","DOI":"10.1021\/acs.jmedchem.5c02014","article-title":"Development of Selective and Soluble Mitochondrial Complex 1 Inhibitors Derived from Papaverine for Radiosensitization of Cancer","volume":"68","author":"Haines","year":"2025","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"157135","DOI":"10.1016\/j.phymed.2025.157135","article-title":"Astragaloside IV alleviates radiation-induced heart disease by regulating energy metabolism","volume":"146","author":"Li","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/s41419-022-04526-0","article-title":"Irradiation causes senescence, ATP release, and P2X7 receptor isoform switch in glioblastoma","volume":"13","author":"Zanoni","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"He, F., Ru, X., and Wen, T. (2020). NRF2, a Transcription Factor for Stress Response and Beyond. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134777"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"114048","DOI":"10.1016\/j.biopha.2022.114048","article-title":"Melatonin inhibits ferroptosis and delays age-related cataract by regulating SIRT6\/p-Nrf2\/GPX4 and SIRT6\/NCOA4\/FTH1 pathways","volume":"157","author":"Mi","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"396","DOI":"10.2174\/1389201024666230823091144","article-title":"Advances on the Role of Ferroptosis in Ionizing Radiation Response","volume":"25","author":"Wang","year":"2024","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1146\/annurev-pharmtox-052220-104025","article-title":"Targeting NRF2 and Its Downstream Processes: Opportunities and Challenges","volume":"62","author":"Torrente","year":"2022","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8317","DOI":"10.21037\/jtd-24-1193","article-title":"Predictive and prognostic value of ACSL4 and GPX4 in patients with esophageal squamous cell carcinoma receiving post-operative radiotherapy","volume":"16","author":"Wang","year":"2024","journal-title":"J. Thorac. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Djuricic, I., and Calder, P.C. (2021). Beneficial Outcomes of Omega-6 and Omega-3 Polyunsaturated Fatty Acids on Human Health: An Update for 2021. Nutrients, 13.","DOI":"10.3390\/nu13072421"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Manosalva, C., Bahamonde, C., Soto, F., Leal, V., Ojeda, C., Cort\u00e9s, C., Alarc\u00f3n, P., and Burgos, R.A. (2024). Linoleic Acid Induces Metabolic Reprogramming and Inhibits Oxidative and Inflammatory Effects in Keratinocytes Exposed to UVB Radiation. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910385"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Mathur, S., Srivastava, P., Srivastava, A., Rai, N.K., Abbas, S., Kumar, A., Tiwari, M., and Sharma, L.K. (2024). Regulation of metastatic potential by drug repurposing and mitochondrial targeting in colorectal cancer cells. BMC Cancer, 24.","DOI":"10.1186\/s12885-024-12064-5"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/6\/780\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T05:00:05Z","timestamp":1782536405000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/6\/780"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,22]]},"references-count":33,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["antiox15060780"],"URL":"https:\/\/doi.org\/10.3390\/antiox15060780","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,22]]}}}