{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:30:30Z","timestamp":1786516230079,"version":"build-2736575974"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>As an independent risk factor for atherosclerosis (AS), hyperhomocysteinemia (HHcy) exerts its pathogenic effects primarily through the induction of macrophage ferroptosis. As a selective autophagic process mediated by nuclear receptor coactivator 4 (NCOA4), ferritinophagy directly influences ferroptosis via its regulation of cellular iron balance. However, whether homocysteine (Hcy) regulates macrophage ferroptosis through ferritinophagy remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human acute monocytic leukemia (THP-1) cells were differentiated into macrophages and subsequently treated with Hcy. Ferroptosis was assessed by measuring glutathione (GSH) levels, reactive oxygen species (ROS), Fe\u00b2\u207a content, and mitochondrial morphology. Protein expression of NCOA4, FTH1, and GPX4 was examined, and GPX4 methylation was evaluated. The involvement of ferritinophagy was further verified using the ferroptosis inhibitor ferrostatin\u20111 (Fer\u20111) and the inducer Erastin. Activation of the IL\u20116\/STAT3 signaling pathway was also examined, along with its reciprocal regulation with ferroptosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Hcy treatment promoted ferroptosis in THP\u20111 macrophages, as indicated by decreased GSH levels, increased ROS and Fe\u00b2\u207a levels, and characteristic mitochondrial morphological changes. Hcy also enhanced GPX4 methylation, resulting in reduced GPX4 expression. Mechanistically, Hcy upregulated NCOA4 and downregulated FTH1, suggesting activation of NCOA4\u2011mediated ferritinophagy; these effects were reversed by Fer\u20111 and augmented by Erastin. In addition, Hcy activated the IL\u20116\/STAT3 pathway, and its crosstalk with ferroptosis was confirmed by the reciprocal modulation with Fer\u20111 and Erastin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Collectively, our study indicates that Hcy promotes ferroptosis in THP-1 macrophages through NCOA4-mediated ferritinophagy, and the IL-6\/STAT3 signaling pathway plays a key role in this process. Therefore, targeting Hcy may represent a potential treatment strategy for AS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphys.2026.1905092","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T05:54:55Z","timestamp":1786514095000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Homocysteine promotes ferroptosis through NCOA4-mediated ferritinophagy in THP-1 macrophages"],"prefix":"10.3389","volume":"17","author":[{"given":"Yu","family":"Yang","sequence":"first","affiliation":[{"name":"Institute of Basic Medicine, North Sichuan Medical College","place":["Nanchong, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiya","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Basic Medicine, North Sichuan Medical College","place":["Nanchong, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Basic Medicine, North Sichuan Medical College","place":["Nanchong, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/nu17081325","article-title":"Homocysteine, nutrition, and gut microbiota: a comprehensive review of current evidence and insights","volume":"17","author":"Agostini","year":"2025","journal-title":"Nutrients"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1038\/s41392-024-02088-5","article-title":"In defence of ferroptosis","volume":"10","author":"Alves","year":"2025","journal-title":"Signal Transduction Targeted Ther."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpc.2022.100456","article-title":"Advanced subclinical atherosclerosis: a novel category within the cardiovascular risk continuum with distinct treatment implications","volume":"13","author":"Blaha","year":"2023","journal-title":"Am. 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