{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:21:37Z","timestamp":1792423297801,"version":"4.5.0"},"reference-count":50,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T00:00:00Z","timestamp":1731888000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>PIEZO1<\/jats:italic>\n                    encodes a mechanoreceptor, a cation channel activated by mechanical stimuli. Gain\u2010of\u2010function (GoF) variants in PIEZO1 cause dehydrated hereditary stomatocytosis (DHS), or xerocytosis, a pleiotropic syndrome characterized by anemia and iron overload. DHS patients develop hepatic iron overload independent of the degree of anemia and transfusion regimen. PIEZO1\u2010GoF variants suppress hepcidin expression in both hepatic cellular model and constitutive\/macrophage\u2010specific Piezo1\u2010GoF mice model. Therefore, PIEZO1\u2010GoF variants regulate hepcidin expression by a crosstalk between hepatocytes (HCs) and macrophages with a still unknown mechanism. Transcriptomic and proteomics analysis in the human hepatic Hep3B cells engineered for the PIEZO1\u2010R2456H variant (PIEZO1\u2010KI) revealed alterations in the actin cytoskeleton regulation, MAPK cascade, and RAS signaling. These changes mainly occur through a novel key regulator, RRAS, whose protein and mRNA levels are regulated by PIEZO1 activation and inhibition. This regulation was further confirmed in C57BL\/6 mouse primary HCs treated with Yoda\u20101 and\/or GsMTx\u20104. Indeed, PIEZO1\u2010KI cells exhibited hyper\u2010activated RAS\u2010GTPase activity that is rescued by PIEZO1 inhibition, restoring expression of the hepcidin gene\n                    <jats:italic>HAMP<\/jats:italic>\n                    . A negative correlation between RAS signaling and\n                    <jats:italic>HAMP<\/jats:italic>\n                    regulation was confirmed by inhibiting RAS\u2010GTPase and MEK1\u20102 activity. Conversely, rescued\n                    <jats:italic>HAMP<\/jats:italic>\n                    gene expression requires downregulation of RRAS, confirming negative feedback between RAS\u2010MAPK and BMP\/SMADs pathways in\n                    <jats:italic>HAMP<\/jats:italic>\n                    regulation. We demonstrated that PIEZO1\u2010GoF variants influence the actin cytoskeleton organization by activating the hepatic RAS signaling system. Understanding the role of RAS signaling in regulating iron metabolism could pave the way for new therapeutic strategies in DHS and other conditions characterized by iron overload.\n                  <\/jats:p>","DOI":"10.1002\/ajh.27523","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T23:30:13Z","timestamp":1731972613000},"page":"52-65","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["RAS signaling pathway is essential in regulating\n                    <scp>PIEZO1<\/scp>\n                    \u2010mediated hepatic iron overload in dehydrated hereditary stomatocytosis"],"prefix":"10.1002","volume":"100","author":[{"given":"Barbara Eleni","family":"Rosato","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies \u201cFederico II\u201d University of Naples  Naples Italy"},{"name":"CEINGE, Biotecnologie Avanzate, Franco Salvatore  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