{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T15:45:29Z","timestamp":1788536729303,"version":"build-2803163510"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background and objective<\/jats:title>\n                    <jats:p>To investigate the role of cardiomyocyte-derived BDNF as an endogenous regulator to decrease cardiac fibrosis, its underlying mechanism and therapeutic potential.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Single-nuclei RNA sequencing (snRNA-seq), KEGG, Gene Ontology and cell\u2012cell interaction analyses were performed to identify changes in cardiac cells, cardiac functions and pathways due to the conditional knockout of cardiomyocyte-derived BDNF (cardiomyocyte-BDNF-KO). Protein C-terminal sequencing, qPCR, WB, CCK8 assays, flow cytometry, BDNF-AAV9 treatment and histological staining were performed to investigate the roles of BDNF and the BDNF mimic 7,8-DHF (7,8-DHF) in cardiac fibroblasts cardiac myofibroblasts and cardiac fibrosis, and the cross-inhibition of the TGF-\u03b2 and BDNF\u2013TrkB-FL pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>snRNA-seq and bioinformatics analysis revealed that cardiomyocyte-BDNF-KO significantly increased the percentage of CFs, decreased the number of cardiomyocytes, and increased the activity of the TGF-\u03b2 pathway in CFs. Functional studies confirmed that compared with those in wild-type hearts, the expression levels of key signaling molecules in the TGF-\u03b2 pathway in cardiomyocyte-BDNF-KO CFs in the mouse heart were significantly higher. CFs and CMFs expressed the BDNF receptor TrkB-FL but not BDNF, and treatment with BDNF and 7,8-DHF decreased the expression of key signaling molecules in the TGF-\u03b2 pathway in CFs and CMFs. BDNF inhibited CF and CMF proliferation, inhibited CF activation and transformation into CMFs, promoted CMF apoptosis, the accumulation of cells in S phase of the cell cycle and TrkB-FL phosphorylation in CFs and CMFs, increased Smad7 expression in CMFs, and inhibited the activity of the TGF-\u03b2\/Smad2\/3\/\u03b1-SMA pathway. 7,8-DHF had the same effects as BDNF, as documented above. Furthermore, BDNF-AAV9 therapy for cardiomyocyte-BDNF-KO hearts increased Smad7 expression and decreased the activity of the TGF-\u03b2\/Smad2\/3 pathway and the expression of fibrotic effectors, which ameliorated cardiac fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Cardiomyocyte-derived BDNF acts as an endogenous mediator to restrict cardiac fibrosis by inhibiting CF and CMF proliferation, CF activation and transformation into CMFs, and increasing arrest in S phase of the cell cycle in CFs and CMFs and the apoptosis of CMFs. The BDNF\u2013TrkB-FL pathway cross-inhibits the activity of the TGF-\u03b2\/Smad2\/3\/\u03b1-SMA pathway and increases the expression of Smad7. BDNF and 7,8-DHF have therapeutic potential for treating cardiac fibrosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1786720","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T05:37:48Z","timestamp":1777354668000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Cardiomyocyte-derived BDNF restricts cardiac fibrosis by decreasing the activity of the TGF-\u03b2\/Smad2\/3 pathway and increasing Smad7 expression"],"prefix":"10.3389","volume":"14","author":[{"given":"Yu","family":"Zhu","sequence":"first","affiliation":[{"name":"Key Laboratory of Regenerative Medicine, Ministry of Education, Jinan University","place":["Guangzhou, China"]},{"name":"Joint Laboratory for Regenerative Medicine, Chinese University of Hong Kong-Jinan University","place":["Guangzhou, China"]},{"name":"International Base of Collaboration for Science and Technology (JNU), The 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