{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:01:38Z","timestamp":1790661698897,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270568"],"award-info":[{"award-number":["82270568"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neurogastroenterology Motil"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Diabetic gastroparesis (DGP) is characterized by delayed gastric emptying and limited mechanism\u2010based therapies. Pyloric dysfunction has been associated with loss of interstitial cells of Cajal (ICC) and altered muscularis macrophage polarization. This study examined whether early growth response 1 (EGR1) links macrophage polarization to ICC integrity in DGP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human full\u2010thickness gastric body transcriptomic data (GSE115601) were analyzed using differential expression and exploratory machine learning, with validation in single\u2010cell RNA sequencing data (GSE252126) and clinical pyloric muscularis biopsies. A streptozotocin\u2010induced DGP rat model was used to test local pyloric adeno\u2010associated virus 9 (AAV9)\u2010mediated EGR1 restoration. Macrophage and primary ICC experiments included EGR1 knockdown, thioredoxin 2 (TXN2) rescue, mitochondrial respiration analysis, cytokine profiling, C\u2010C motif chemokine ligand 5 (CCL5) neutralization, and C\u2010C chemokine receptor 5 (CCR5) blockade.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      EGR1 was downregulated in DGP gastric body samples and subsequently validated in human pyloric muscularis biopsies, with enrichment in macrophages, particularly M2 macrophages. EGR1 loss reduced TXN2 transcription and mitochondrial oxidative phosphorylation (OXPHOS), impaired M2 polarization, and increased macrophage CCL5 secretion. Conditioned medium from EGR1\u2010deficient macrophages induced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      dysregulation, NLR family pyrin domain containing 3 (NLRP3) activation, and ICC marker loss; these effects were attenuated by CCL5 neutralization or CCR5 blockade. Local AAV9\u2010EGR1 restoration increased M2 macrophage and ICC marker expression, improved gastric emptying, and regularized pyloric slow waves without improving systemic glucose control.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Muscularis EGR1 deficiency may promote DGP by disrupting TXN2\u2010dependent macrophage OXPHOS and triggering CCL5\/CCR5\/NLRP3\u2010mediated ICC injury. Local EGR1 restoration improved gastric motility and may represent a therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/nmo.70439","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T03:48:32Z","timestamp":1789530512000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Muscularis\n                    <scp>EGR1<\/scp>\n                    Deficiency Impairs\n                    <scp>M2<\/scp>\n                    Macrophage Polarization and Disrupts Gastric Motility in Diabetic Gastroparesis"],"prefix":"10.1111","volume":"38","author":[{"given":"Ni","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai 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