{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:27:34Z","timestamp":1788344854768,"version":"build-2803163510"},"reference-count":84,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T00:00:00Z","timestamp":1666915200000},"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":["32172808"],"award-info":[{"award-number":["32172808"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>L-citrulline (L-cit) is a key intermediate in the urea cycle and is known to possess antioxidant and anti-inflammation characteristics. However, the role of L-cit in ameliorating oxidative damage and immune dysfunction against iron overload in the thymus remains unclear. This study explored the underlying mechanism of the antioxidant and anti-inflammation qualities of L-cit on iron overload induced in the thymus. We reported that L-cit administration could robustly alleviate thymus histological damage and reduce iron deposition, as evidenced by the elevation of the CD8+ T lymphocyte number and antioxidative capacity. Moreover, the NF-\u03baB pathway, NCOA4-mediated ferritinophagy, and ferroptosis were attenuated. We further demonstrated that L-cit supplementation significantly elevated the mTEC1 cells\u2019 viability and reversed LDH activity, iron levels, and lipid peroxidation caused by FAC. Importantly, NCOA4 knockdown could reduce the intracellular cytoplasmic ROS, which probably relied on the Nfr2 activation. The results subsequently indicated that NCOA4-mediated ferritinophagy was required for ferroptosis by showing that NCOA4 knockdown reduced ferroptosis and lipid ROS, accompanied with mitochondrial membrane potential elevation. Intriguingly, L-cit treatment significantly inhibited the NF-\u03baB pathway, which might depend on restraining ferritinophagy-mediated ferroptosis. Overall, this study indicated that L-cit might target ferritinophagy-mediated ferroptosis to exert antioxidant and anti-inflammation capacities, which could be a therapeutic strategy against iron overload-induced thymus oxidative damage and immune dysfunction.<\/jats:p>","DOI":"10.3390\/nu14214549","type":"journal-article","created":{"date-parts":[[2022,10,30]],"date-time":"2022-10-30T09:01:42Z","timestamp":1667120502000},"page":"4549","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["L-Citrulline Supplementation Restrains Ferritinophagy-Mediated Ferroptosis to Alleviate Iron Overload-Induced Thymus Oxidative Damage and Immune Dysfunction"],"prefix":"10.3390","volume":"14","author":[{"given":"Tongtong","family":"Ba","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dai","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqin","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuiping","family":"Zeng","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai","family":"Niu","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6753-9703","authenticated-orcid":false,"given":"Hanchuan","family":"Dai","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"627662","DOI":"10.3389\/fimmu.2020.627662","article-title":"The Clinical Significance of Iron Overload and Iron Metabolism in Myelodysplastic Syndrome and Acute Myeloid Leukemia","volume":"11","author":"Weber","year":"2021","journal-title":"Front. 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