{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:28:29Z","timestamp":1792794509252,"version":"4.5.0"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Nanyang Assistant Professorship"},{"name":"Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 1","award":["RG25\/20"],"award-info":[{"award-number":["RG25\/20"]}],"id":[{"id":"https:\/\/ror.org\/01kcva023","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Singapore Ministry of Health's National Medical Research Council under its Open Fund\u2014Individual Research Grant","award":["MOH-001495"],"award-info":[{"award-number":["MOH-001495"]}],"id":[{"id":"https:\/\/ror.org\/04x3cxs03","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Vascular Research Initiative"},{"name":"Nanyang President's Graduate Scholarship from Nanyang Technological University Singapore","id":[{"id":"https:\/\/ror.org\/02e7b5302","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Neutrophils release their chromatin with toxic granular proteins as neutrophil extracellular traps (NETs) when activated. Diabetes exacerbates NET formation (NETosis), resulting in tissue damage and diabetic complications such as nonhealing wounds. How diabetes predisposes neutrophils to NETosis remains unclear. Herein, we found that pharmacological inhibition or siRNA knockdown of sirtuin 1 (SIRT1) increased NETosis in neutrophils of healthy humans and mice, unveiling SIRT1 as an endogenous suppressor of NETosis. In contrast, SIRT1 inhibition did not cause further increase in NETosis in neutrophils of humans and mice with diabetes, indicative of SIRT1 dysfunction in a disease state. Indeed, SIRT1 deacetylase activity was significantly lower in neutrophils of individuals with diabetes, accompanied by a concomitant increase in the activity of peptidylarginine deiminase 4 (PAD4), a key enzyme that mediates NETosis. PAD4 was codetected with SIRT1 immunoprecipitated from neutrophils isolated from healthy individuals and HL-60\u2013derived neutrophils (dHL-60) cultured in basal glucose; such co-immunoprecipitation was absent in neutrophils of individuals with diabetes and dHL-60 cells treated with high levels of glucose, suggesting that hyperglycemia disrupts the SIRT1\u2013PAD4 interaction. SIRT1 activators restored the SIRT1\u2013PAD4 interaction and normalized the exacerbated NETosis and PAD4 activity in diabetes and hyperglycemia, culminating in improved diabetic wound healing. This study reveals a novel regulatory role of SIRT1 on PAD4 activity. Revitalizing SIRT1 can be a new preventive or therapeutic strategy for combating NET-mediated inflammation in diabetes and beyond.<\/jats:p>","DOI":"10.1093\/jleuko\/qiag006","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T12:43:12Z","timestamp":1768394592000},"source":"Crossref","is-referenced-by-count":3,"title":["Sirtuin 1 is an endogenous NETosis inhibitor that becomes dysfunctional in diabetes"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0408-2010","authenticated-orcid":false,"given":"Liang De","family":"Wang","sequence":"first","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University \u00a0 Singapore, 11 Mandalay Road , 308232","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8134-1204","authenticated-orcid":false,"given":"Feng","family":"Chen","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University \u00a0 Singapore, 11 Mandalay Road , 308232","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinkoo","family":"Dalan","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University \u00a0 Singapore, 11 Mandalay Road , 308232","place":["Singapore"]},{"name":"Department of Endocrinology, Tan Tock Seng Hospital , 11 Jalan Tan Tock Seng , 308433","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han Wei","family":"Hou","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University \u00a0 Singapore, 11 Mandalay Road , 308232","place":["Singapore"]},{"name":"School of Mechanical and Aerospace Engineering, Nanyang Technological University \u00a0 Singapore, 50 Nanyang Avenue , 639798","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2294-3187","authenticated-orcid":false,"given":"Siu Ling","family":"Wong","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University \u00a0 Singapore, 11 Mandalay Road , 308232","place":["Singapore"]},{"name":"Tan Tock Seng Hospital , 11 Jalan Tan Tock Seng , 308433","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,1,19]]},"reference":[{"key":"2026031813370490900_qiag006-B1","doi-asserted-by":"publisher","first-page":"7326","DOI":"10.1073\/pnas.1909546117","article-title":"NETosis proceeds by cytoskeleton and endomembrane disassembly and PAD4-mediated chromatin decondensation and nuclear envelope rupture","volume":"117","author":"Thiam","year":"2020","journal-title":"Proc Natl Acad Sci U S 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