{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:02:00Z","timestamp":1792087320675,"version":"4.4.0"},"reference-count":36,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Nephrology"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Neutrophil extracellular trap formation (NETosis) has been recognised to participate in the pathogenesis of septic acute kidney injury (SAKI). However, the molecular regulatory mechanism of NETosis in SAKI remains poorly understood. This study explored the role and potential mechanism of peptidyl arginine deiminase 4 (PAD4) in NETosis during SAKI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Sepsis rat model induced by cecal ligation and puncture (CLP) and lipopolysaccharides (LPS)\u2010stimulated NRK\u201052E cells were used to mimic SAKI in\u00a0vivo and in\u00a0vitro. Kidney injury was evaluated by haematoxylin and eosin (HE) staining and serum urea nitrogen and creatinine levels. Serum lactate level was assessed by enzyme\u2010linked immunosorbent assay (ELISA). Target molecule expression was determined by quantitative real\u2010time polymerase chain reaction (qRT\u2010PCR) and Western blotting. Citrullinated histone H3 (citH3) expression was observed by immunofluorescent staining. The binding of p300 to the PAD4 promoter was analysed by chromatin immunoprecipitation (ChIP).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      PAD4 and serum lactate levels were elevated in SAKI rats by two folds and one fold, respectively (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), which exhibited a positive correlation (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). H3K18 lactylation level was doubled in the kidneys of CLP rats (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Moreover, p300\u2010mediated H3K18 lactylation contributed to PAD4 expression in response to LPS stimulation (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Finally, inhibition of PAD4 or histone lactylation suppressed NETosis (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), thereby alleviating SAKI in rats.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>p300\u2010mediated H3K18 lactylation enhanced PAD4 expression to facilitate SAKI by promoting NETosis. Our findings provide a theoretical basis for PAD4 as a promising therapeutic target for SAKI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/nep.70137","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T08:06:07Z","timestamp":1760688367000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Histone Lactylation\u2010Mediated\n                    <scp>PAD4<\/scp>\n                    Up\u2010Regulation Promotes Septic Acute Kidney Injury via Activating\n                    <scp>NETosis<\/scp>"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2229-2521","authenticated-orcid":false,"given":"Wen\u2010lin","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Urology Zhuzhou Hospital, Xiangya Medical College, Central South University  Zhuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan\u2010chen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy Zhuzhou Hospital, Xiangya Medical College, Central South University  Zhuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian\u2010le","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Urology Zhuzhou Hospital, Xiangya Medical College, Central South University  Zhuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Urology Zhuzhou Hospital, Xiangya Medical College, Central South University  Zhuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi\u2010wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology Zhuzhou Hospital, Xiangya Medical College, Central South University  Zhuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1001-2416","authenticated-orcid":false,"given":"Yong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Urology Zhuzhou Hospital, Xiangya Medical College, Central South University  Zhuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-025-05253-6"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/0886022X.2022.2138433"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-023-00957-9"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00081"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.61902"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00089.2019"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.89740"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700639"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1678-1"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.949252"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202307216"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00975"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.4055\/cios.2014.6.1.103"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.4103\/0366-6999.209889"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40635-017-0130-9"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1590\/s0102-865020190010000003"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12670"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-024-01327-0"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.777665"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103246"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adn2108"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12882-020-01974-8"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccc.2020.11.010"},{"key":"e_1_2_10_25_1","first-page":"616","article-title":"Protein Arginine Deiminase 4 (PAD4): Current Understanding and Future Therapeutic Potential","volume":"12","author":"Jones J. 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