{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:46:05Z","timestamp":1790189165137,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T00:00:00Z","timestamp":1723075200000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81930108"],"award-info":[{"award-number":["81930108"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271347"],"award-info":[{"award-number":["82271347"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chronic inflammation contributes to the progression of isoproterenol (ISO)\u2010induced heart failure (HF). Caspase\u2010associated recruitment domain (CARD) families are crucial proteins for initiation of inflammation in innate immunity. Nonetheless, the relevance of CARDs in ISO\u2010driven cardiac remodelling is little explored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study utilized Card9\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice and reconstituted C57BL\/6 mice with either Card9\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      or Otud1\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      marrow\u2010derived cells. Mechanistic studies were conducted in primary macrophages, cardiomyocytes, fibroblasts and HEK\u2010293T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Here, we demonstrated that CARD9 was substantially upregulated in murine hearts infused with ISO. Either whole\u2010body CARD9 knockout or myeloid\u2010specific CARD9 deletion inhibited ISO\u2010driven murine cardiac inflammation, remodelling and dysfunction. CARD9 deficiency in macrophages prevented ISO\u2010induced inflammation and alleviated remodelling changes in cardiomyocytes and fibroblasts. Mechanistically, we found that ISO enhances the activity of CARD9 by upregulating ovarian tumour deubiquitinase 1 (OTUD1) in macrophages. We further demonstrated that OTUD1 directly binds to the CARD9 and then removes the K33\u2010linked ubiquitin from CARD9 to promote the assembly of the CARD9\u2010BCL10\u2010MALT1 (CBM) complex, without affecting CARD9 stability. The ISO\u2010activated CBM complex results in NF\u2010\u03baB activation and macrophage\u2010based inflammatory gene overproduction, which then enhances cardiomyocyte hypertrophy and fibroblast fibrosis, respectively. Myeloid\u2010specific OTUD1 deletion also attenuated ISO\u2010induced murine cardiac inflammation and remodelling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results suggested that the OTUD1\u2010CARD9 axis is a new pro\u2010inflammatory signal in ISO\u2010challenged macrophages and targeting this axis has a protective effect against ISO\u2010induced HF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Macrophage CARD9 was elevated in heart tissues of mice under chronic ISO administration.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Either whole\u2010body CARD9 knockout or myeloid\u2010specific CARD9 deficiency protected mice from ISO\u2010induced inflammatory heart remodeling.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>ISO promoted the assembly of CBM complex and then activated NF\u2010\u03baB signaling in macrophages through OTUD1\u2010mediated deubiquitinating modification.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>OTUD1 deletion in myeloid cells protected hearts from ISO\u2010induced injuries in mice.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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