{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:08:25Z","timestamp":1789013305231,"version":"build-2803163510"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,8,4]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Cardiac fibrosis is a hallmark of ischemic heart failure and is driven by activated myofibroblasts. DNA damage and defective repair promote fibroblast activation, yet the upstream regulators that couple DNA damage responses to profibrotic remodeling remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Single\u2010cell RNA sequencing data sets from human ischemic cardiomyopathy were analyzed to identify fibroblast\u2010enriched candidate genes. In\u00a0vivo,\n                      <jats:italic toggle=\"no\">Postn<\/jats:italic>\n                      promoter\u2010driven adeno\u2010associated viruses were used to knock down or overexpress CRABP2 (cellular retinoic acid\u2010binding protein 2) in an isoproterenol\u2010induced mouse model, followed by assessment of ventricular function and fibrosis. In\u00a0vitro, neonatal cardiac fibroblasts were subjected to CRABP2 gain or loss of function and TGF\u2010\u03b2 (transforming growth factor\u2010\u03b2) stimulation. Mechanistic studies combined RNA sequencing, immunoprecipitation\u2013mass spectrometry, structural modeling, \u03b3\u2010H2AX staining, comet assays, and MRE11\/MRE11\u2010RAD50\u2010NBS1 (MRN) perturbation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Single\u2010cell analyses identify\n                      <jats:italic toggle=\"no\">CRABP2<\/jats:italic>\n                      as a fibroblast\u2010enriched gene upregulated in profibrotic fibroblast subsets in human ischemic hearts. In\u00a0vivo,\n                      <jats:italic toggle=\"no\">CRABP2<\/jats:italic>\n                      knockdown in\n                      <jats:italic toggle=\"no\">Postn<\/jats:italic>\n                      <jats:sup>+<\/jats:sup>\n                      myofibroblasts preserves left ventricular function and attenuates interstitial fibrosis, whereas\n                      <jats:italic toggle=\"no\">CRABP2<\/jats:italic>\n                      overexpression exacerbates dysfunction and fibrosis in isoproterenol\u2010treated mice. In\u00a0vitro,\n                      <jats:italic toggle=\"no\">CRABP2<\/jats:italic>\n                      promotes TGF\u2010\u03b2\u2013induced fibroblast migration, proliferation, activation, and collagen production. Mechanistically,\n                      <jats:italic toggle=\"no\">CRABP2<\/jats:italic>\n                      binds MRE11, suppresses MRN\u2010ATM\u2010CHK2 signaling, and enhances DNA damage accumulation. Inhibiting or silencing MRE11 abrogates the antifibrotic and cardioprotective effects of\n                      <jats:italic toggle=\"no\">CRABP2<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      <jats:italic toggle=\"no\">CRABP2<\/jats:italic>\n                      drives profibrotic cardiac fibroblast activation by inhibiting MRE11\/MRN\u2010mediated DNA repair. The CRABP2\u2010MRE11\u2010MRN axis represents a potential therapeutic target for limiting fibrotic remodeling in ischemic heart failure.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.126.049049","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T11:16:24Z","timestamp":1785496584000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Cellular Retinoic Acid\u2013Binding Protein 2 Promotes Ischemia\u2010Induced Cardiac Fibroblast Activation and Fibrosis Through Suppression of MRE11\u2010RAD50\u2010NBS1\u2013Mediated DNA Repair"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4064-1772","authenticated-orcid":false,"given":"Zhenyang","family":"Su","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital with Nanjing Medical University","place":["Nanjing, 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