{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T18:39:48Z","timestamp":1792435188858,"version":"4.5.0"},"reference-count":65,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"16","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,10,20]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Myocardial ischemia\/reperfusion injury triggers profound metabolic reprogramming and lactate accumulation. However, how this metabolic stress regulates inflammatory gene expression remains poorly understood. We hypothesized that lactylation, a lactate-derived posttranslational modification, links metabolic stress to aberrant RNA splicing and cardiac inflammation through the RNA-binding protein HNRNPK (heterogeneous nuclear ribonucleoprotein K).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We analyzed atrial tissues from patients undergoing cardiopulmonary bypass and murine ischemia\/reperfusion hearts to assess lactylation dynamics. Lactylation-specific proteomics, RNA sequencing, and crosslinking and immunoprecipitation followed by quantitative polymerase chain reaction were used to identify HNRNPK targets. Mechanisms were defined using site-directed mutagenesis (HNRNPK-K405R), isoform-specific overexpression, and a therapeutic splice-switching antisense oligonucleotide in mice and cardiomyocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Reperfusion significantly increased global protein lactylation in human and murine myocardium. Proteomics identified HNRNPK as a key target, specifically lactylated at lysine 405 (K405la). Ischemia-induced K405la promoted HNRNPK binding to\n                      <jats:italic toggle=\"yes\">Jag2<\/jats:italic>\n                      pre-mRNA, suppressing exon 10 skipping and shifting splicing from the\n                      <jats:italic toggle=\"yes\">Jag2<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">Jagged2<\/jats:italic>\n                      ) short (\n                      <jats:italic toggle=\"yes\">Jag2<\/jats:italic>\n                      -S) to the long (\n                      <jats:italic toggle=\"yes\">Jag2<\/jats:italic>\n                      -L) isoform. Jag2-L, but not Jag2-S, exhibited high affinity for Notch1, hyperactivating Notch\u2013NF-\u03baB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling and exacerbating inflammation and infarct size. Mice expressing a lactylation-deficient variant (HNRNPK-K405R) were protected from ischemia\/reperfusion injury. Treatment with a specific antisense oligonucleotide (Jag2-i9) that blocks the HNRNPK\u2013\n                      <jats:italic toggle=\"yes\">Jag2<\/jats:italic>\n                      interaction prevented Jag2-L production and attenuated cardiac dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      HNRNPK lactylation acts as a metabolic sensor coupling lactate accumulation to pathogenic\n                      <jats:italic toggle=\"yes\">Jag2<\/jats:italic>\n                      splicing. Targeting this metabolic\u2013splicing axis offers a precise therapeutic strategy to limit inflammation and preserve cardiac function in ischemic heart disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>REGISTRATION:<\/jats:title>\n                    <jats:p>\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.chictr.org.cn\">http:\/\/www.chictr.org.cn<\/jats:ext-link>\n                      ; Unique identifier: ChiCTR2400091959.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.126.081410","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T09:01:50Z","timestamp":1788858110000},"page":"1604-1623","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["HNRNPK Lactylation Amplifies Inflammation and Exacerbates Myocardial Ischemia\/Reperfusion Injury by Regulating Jag2 Splicing"],"prefix":"10.1161","volume":"154","clinical-trial-number":[{"clinical-trial-number":"chictr2400091959","registry":"10.18810\/chictr"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3111-3430","authenticated-orcid":true,"given":"Suyun","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1192-7904","authenticated-orcid":true,"given":"Siman","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenmei","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linhang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianning","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqiang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3815-0234","authenticated-orcid":true,"given":"Kun","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruizhao","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8180-2193","authenticated-orcid":true,"given":"Yaofeng","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9385-7393","authenticated-orcid":true,"given":"Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Cancer Stem Cell, Dalian Medical University, Liaoning, China (Y. 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