{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T12:37:12Z","timestamp":1791376632409,"version":"4.3.2"},"reference-count":56,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,12,9]],"date-time":"2019-12-09T00:00:00Z","timestamp":1575849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008594","name":"European Hematology Association","doi-asserted-by":"publisher","award":["3978026"],"award-info":[{"award-number":["3978026"]}],"id":[{"id":"10.13039\/100008594","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Dehydrated hereditary stomatocytosis (DHS), or xerocytosis, is an autosomal dominant hemolytic anemia. Most patients with DHS carry mutations in the\n                    <jats:italic>PIEZO1<\/jats:italic>\n                    gene encoding a mechanosensitive cation channel. We here demonstrate that patients with DHS have low levels of hepcidin and only a slight increase of ERFE, the erythroid negative regulator of hepcidin. We demonstrated that at the physiological level, PIEZO1 activation induced Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx and suppression of\n                    <jats:italic>HAMP<\/jats:italic>\n                    expression in primary hepatocytes. In two hepatic cellular models expressing PIEZO1 WT and two PIEZO1 gain\u2010of\u2010function mutants (R2456H and R2488Q), we highlight altered expression of a few genes\/proteins involved in iron metabolism. Mutant cells showed increased intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    compared to WT, which was correlated to increased phosphorylation of ERK1\/2, inhibition of the BMP\u2010SMADs pathway, and suppression of\n                    <jats:italic>HAMP<\/jats:italic>\n                    transcription. Moreover, the HuH7 cells, treated with PD0325901, a potent inhibitor of ERK1\/2 phosphorylation, reduced the phosphorylation of ERK1\/2 with the consequent increased phosphorylation of SMAD1\/5\/8, confirming the link between the two pathways. Another \u201cproof of concept\u201d for the mechanism that links PIEZO1 to\n                    <jats:italic>HAMP<\/jats:italic>\n                    regulation was obtained by mimicking PIEZO1 activation by cell Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload, by the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ionophore A23187. There was strong down\u2010regulation of\n                    <jats:italic>HAMP<\/jats:italic>\n                    gene expression after this Ca\n                    <jats:sup>2+<\/jats:sup>\n                    overload. Finally, the inhibition of PIEZO1 by GsMTx4 leads to phenotype rescue. This is the first demonstration of a direct link between PIEZO1 and iron metabolism, which defines the channel as a new hepatic iron metabolism regulator and as a possible therapeutic target of iron overload in DHS and other iron\u2010loading anemias.\n                  <\/jats:p>","DOI":"10.1002\/ajh.25683","type":"journal-article","created":{"date-parts":[[2019,11,18]],"date-time":"2019-11-18T05:15:12Z","timestamp":1574054112000},"page":"188-197","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Gain\u2010of\u2010function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP\/SMADs pathway"],"prefix":"10.1002","volume":"95","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0493-812X","authenticated-orcid":false,"given":"Immacolata","family":"Andolfo","sequence":"first","affiliation":[{"name":"Dipartimento di Medicina Molecolare e Biotecnologie Mediche Universit\u00e0 degli 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