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Although G6PD deficiency is a prevalent enzyme defect worldwide, the specific role of G6PD itself in platelets remains unclear. Herein, we discover a previously unrecognized phenotype in both human patients and murine models, demonstrating that G6PD deficiency leads to elevated platelet counts through enhanced proplatelet formation (PPF). Mechanistically, we reveal a non-canonical function of G6PD in regulating actin dynamics via its interaction with an actin-binding protein, tropomodulin-3 (TMOD3). The G6PD-TMOD3 interaction, which is concentration-dependently enhanced by nicotinamide adenine dinucleotide phosphate (NADP\n                    <jats:sup>+<\/jats:sup>\n                    ), can limit actin rearrangement, thereby inhibiting PPF. Furthermore, we develop a G6PD-derived peptide, GC2P2, which potentiates the G6PD-TMOD3 interaction and significantly suppresses thrombocytopoiesis both in vitro and in vivo. In conclusion, our findings suggest that G6PD deficiency facilitates platelet biogenesis by altering TMOD3-mediated actin dynamics. The study provides new insights into thrombopoiesis and offers potential strategies for modulating platelet production.\n                  <\/jats:p>","DOI":"10.1038\/s44319-026-00962-7","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:02:39Z","timestamp":1791896559000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["G6PD suppresses thrombopoiesis via interfering with TMOD3-mediated actin dynamics"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3099-5960","authenticated-orcid":false,"given":"Min","family":"Xin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7338-5329","authenticated-orcid":false,"given":"Chihao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5787-1777","authenticated-orcid":false,"given":"Peipei","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0034-2218","authenticated-orcid":false,"given":"Yanyan","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9879-0829","authenticated-orcid":false,"given":"Changming","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoming","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haojie","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junling","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9609-4117","authenticated-orcid":false,"given":"Xuefeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8152-7423","authenticated-orcid":false,"given":"Yanyan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2289-5760","authenticated-orcid":false,"given":"Jing","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"key":"962_CR1","doi-asserted-by":"publisher","first-page":"17238","DOI":"10.3390\/ijms242417238","volume":"24","author":"A Ahamed","year":"2023","unstructured":"Ahamed A, Hosea R, Wu S, Kasim V (2023) The emerging roles of the metabolic regulator G6PD in human cancers. 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