{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T09:41:41Z","timestamp":1766050901149,"version":"3.46.0"},"reference-count":67,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T00:00:00Z","timestamp":1751155200000},"content-version":"vor","delay-in-days":28,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Sodium\/glucose cotransporter 2 inhibitors (SGLT2i) protect against heart failure and fibroinflammation with an unclear mechanistic. Recombinant interleukin\u201011 (IL11) therapy for thrombocytopenia induces heart failure symptoms and signs. Profibrotic IL11 upregulates extracellular matrix (ECM) proteins, whereas pro\u2010inflammatory tenascin\u2010C (TNC) is an ECM\u2010derived alarmin. We hypothesized IL11 upregulated TNC to induce fibroinflammation via Toll\u2010like receptor 4 (TLR4) and prototype SGLT2i dapagliflozin counteracted the effects. We stimulated fibroblasts with IL11 and confirmed TNC upregulation. NADPH oxidase 2 (NOX2) is known to participate in TNC\u2010TLR4 signaling. We treated IL11\u2010stimulated fibroblasts with inhibitors of TLR4 (TLR4i) and NOX2 (NOX2i) and found IL11 induced an imperative profibrotic TNC\u2010TLR4\u2010NOX2 auto\u2010amplification loop. IL11 is known to induce ERK\u2010dependent positive autofeedback. By finding TLR4i and NOX2i inhibited IL11\u2010induced ERK phosphorylation, we suspected IL11\u2010ERK joined TNC\u2010TLR4\u2010NOX2 auto\u2010amplification fibroinflammatory pathway. We stimulated fibroblasts with TNC and found IL11 upregulation. We treated TNC\u2010stimulated fibroblasts with TLR4i, NOX2i, or neutralizing IL11 antibody and confirmed TLR4\u2010NOX2 and IL11 were indispensable for TNC\u2010induced fibrosis. We concluded that IL11\u2010ERK, TNC\u2010TLR4, and NOX2 are interdependent in fibroblasts and together make a positive\u2010feedback loop to sustain fibroinflammation. We checked mRNA expression of relevant proteins from\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/proteinatlas.org\">proteinatlas.org<\/jats:ext-link>\n                    and found fibroblasts are overwhelming producers of IL11 and TNC in the heart. IL11 receptor subunit alpha (IL11RA) and TLR4 are highly differentially expressed with the former on cardiomyocytes and the latter on macrophages. We therefore proposed a model of differentially activated IL11RA and TLR4 signaling in response to mutually reinforcing IL11\u2010TNC alarmins, to explain how activated fibroblasts pivotally support fibroinflammatory microenvironment and how danger signals induce cell\u2010type\u2010specific responses. Next, we showed dapagliflozin prevented fibroinflammation induced by IL11 or TNC. Mechanistically, we showed dapagliflozin antagonized IL11RA by molecular docking, fluorescence quenching, and grading\u2010dose IL11\u2010signaling inhibitor cocktails studies. In conclusion, dapagliflozin interrupts pro\u2010fibroinflammatory IL11\u2010TNC bi\u2010alarmin mutual reinforcement in human cardiac fibroblasts by antagonizing IL11RA.\n                  <\/jats:p>","DOI":"10.1002\/jcp.70052","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T01:29:24Z","timestamp":1751246964000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dapagliflozin Interrupts Pro\u2010Fibroinflammatory Interleukin 11\u2010Tenascin C Mutual Reinforcement in Fibroblasts by Antagonizing Interleukin\u201011 Receptor Subunit Alpha"],"prefix":"10.1002","volume":"240","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4364-2727","authenticated-orcid":false,"given":"Yen\u2010Chen","family":"Lin","sequence":"first","affiliation":[{"name":"Graduate Institute of Clinical Medical Sciences, College of Medicine Chang Gung University Taoyuan Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine Linkou Chang Gung Memorial Hospital Taoyuan Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei\u2010Jan","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Linkou Chang Gung Memorial Hospital Taoyuan Taiwan"},{"name":"School of Medicine, College of Medicine Chang Gung University Taoyuan Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu\u2010Juei","family":"Hsu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine Tri\u2010Service General Hospital Taipei Taiwan"},{"name":"Department of Biochemistry National Defense Medical Center Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying\u2010Ju","family":"Lai","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine Linkou Chang Gung Memorial Hospital Taoyuan 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