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Cyclovirobuxine D (CVB-D) is a naturally occurring bioactive alkaloid derived from\n                      <jats:italic>Buxus microphylla<\/jats:italic>\n                      . Emerging evidence suggests that CVB-D may ameliorate diabetes-associated cardiomyocyte failure. However, the protective effects of CVB-D against cardiomyocyte failure have not been extensively investigated, and the underlying molecular mechanisms remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A mouse model of diabetic cardiomyopathy was established by combining a high-fat diet (HFD) with streptozotocin (STZ). To examine the In vivo contribution of JAK1, AAV9 vectors targeting JAK1 were administered via tail-vein injection, with the corresponding negative-control vectors used in parallel. In vitro, a cardiomyocyte injury model was generated by exposing neonatal mouse ventricular myocytes (NMVMs) to palmitate and high-glucose (PA\/HG) conditions. The cardioprotective effects of CVB-D were evaluated using Western blotting, flow cytometry, immunofluorescence microscopy, mitochondrial respiration assays, and ELISA-based measurements. Mechanistic investigations further integrated molecular docking, immunoprecipitation (IP), microscale thermophoresis (MST), surface plasmon resonance (SPR), and liquid chromatography-tandem mass spectrometry (LC-MS\/MS) to define the molecular targets and JAK1\/STAT1 signaling pathways underlying CVB-D activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CVB-D treatment robustly improved mitochondrial dysfunction in Diabetic cardiomyopathy and attenuated heart failure-like phenotypes in cardiomyocytes both in vivo and in vitro. Mechanistically, CVB-D reduced JAK1 expression and concomitantly diminished STAT1 phosphorylation, thereby alleviating cardiomyocyte injury. Moreover, convergent evidence from IP, MST, and SPR assays supported a central role for the JAK1-STAT1 axis in mediating the functional effects of CVB-D. LC-MS\/MS analysis further identified STAT1 residues T598 and T699 as putative JAK1-dependent phosphorylation regulatory sites in NMVMs. Consistently, genetic knockdown or pharmacological inhibition of JAK1 improved DCM-related phenotypes, whereas enforced JAK1 expression or pharmacological activation blunted the protective effects of CVB-D, indicating that CVB-D-mediated cardioprotection requires suppression of JAK1-STAT1 signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings indicate that CVB-D enhances mitochondrial function by suppressing the JAK1-STAT1 signaling axis, thereby ameliorating heart failure associated with DCM. These results suggest that CVB-D may represent a promising therapeutic candidate for the treatment of DCM-related heart failure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s13020-026-01411-2","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T08:51:15Z","timestamp":1778662275000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CVB-D attenuates experimental diabetic cardiomyopathy by alleviating mitochondrial dysfunction via the JAK1-STAT1 signaling axis in vivo and in vitro"],"prefix":"10.1186","volume":"21","author":[{"given":"Hang","family":"Su","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun-qiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiang-fei","family":"An","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue-ting","family":"Tuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting-ting","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling-yun","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-bing","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Tao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-ni","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang-chun","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"1411_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1401961","volume":"15","author":"X P","year":"2024","unstructured":"P X, H E, Z F, et al. 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