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Hepcidin (a peptide hormone) plays a principal role in regulating intracellular iron levels by modulating ferroportin (FPN, the only known iron exporter) through triggering its internalization and lysosomal degradation. We observed a significant and rapid iron surge in the cortices of ischemic hemispheres at 3\u2009h after cerebral ischemia (middle cerebral artery occlusion, MCAO) that was maintained until 4 d post-MCAO. We showed upregulation of hepcidin expression in the brain as early as 3\u2009h post-MCAO, mainly in astrocytes, and significant hepcidin accumulation in serum from 6\u2009h post-MCAO, and these inductions were maintained for 1 day and 7 days, respectively. High mobility group box 1 (HMGB1), a prototypic danger-associated molecular pattern, accumulates markedly after transient MCAO and plays critical roles in damage aggravation via its proinflammatory effects. Here, we demonstrated that treatment with recombinant HMGB1 stimulated astrocytes to induce hepcidin expression in a TLR4- and CXCR4-dependent manner. Furthermore, hepcidin-mediated intracellular iron accumulation in neurons was confirmed by an experiment using N-methyl-D-aspartate (NMDA)-conditioned medium-treated primary astrocytes and fresh primary cortical neurons treated with hepcidin-containing astrocyte-conditioned medium. Moreover, HMGB1-mediated local hepcidin upregulation and subsequent local iron surge were found to cause ferroptosis in the postischemic brain, which was suppressed by the functional blocking of HMGB1 using intranasally administered HMGB1 A box or anti-HMGB1 antibody. These findings show that HMGB1 serves as a ferroptosis inducer by upregulating hepcidin in astrocytes and thus aggravates acute damage in the postischemic brain.<\/jats:p>","DOI":"10.1038\/s12276-023-01111-z","type":"journal-article","created":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T01:02:28Z","timestamp":1698800548000},"page":"2402-2416","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["HMGB1 induces hepcidin upregulation in astrocytes and causes an acute iron surge and subsequent ferroptosis in the postischemic brain"],"prefix":"10.1038","volume":"55","author":[{"given":"Dashdulam","family":"Davaanyam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hahnbi","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song-I","family":"Seol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-A","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Woo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ja-Kyeong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,1]]},"reference":[{"key":"1111_CR1","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1089\/ars.2012.4931","volume":"20","author":"NS Singh","year":"2014","unstructured":"Singh, N. 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