{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T20:13:46Z","timestamp":1788380026248,"version":"build-2803163510"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,3,27]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Pathogenic cardiac hypertrophy, often driven by mechanical stress, is a leading cause of heart failure. However, effective therapeutic targets remain limited. TMC6 (transmembrane channel-like protein 6) is abundant in healthy myocardium but downregulated in hypertrophic hearts; its role in cardiac hypertrophy remains undefined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We combined cardiac-specific\n                      <jats:italic toggle=\"yes\">Tmc6<\/jats:italic>\n                      knockout mice subjected to transverse aortic constriction surgery, neonatal rat ventricular myocytes, and CRISPR\/Cas9-edited human pluripotent stem cell-derived cardiomyocytes to assess hypertrophy and signaling readouts. Subcellular localization, protein\u2013protein interaction, and competitive peptide assays were used to dissect the mechanism. Adeno-associated virus serotype 9 (AAV9)-cTnT (cardiac troponin T)-TMC6 was used for in vivo rescue.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      TMC6 deficiency increased cardiomyocyte size, fetal gene expression, and adverse remodeling in vivo and in vitro, whereas TMC6 overexpression blunted hypertrophic responses. Full-length TMC6 localized to the endoplasmic reticulum and bound CIB1 (calcium and integrin-binding protein 1) to sequester it in the endoplasmic reticulum, limiting CIB1 access to sarcolemmal Ca\n                      <jats:sup>2+<\/jats:sup>\n                      microdomains required to scaffold calcineurin and activate NFAT (nuclear factor of activated T cells). A cell-permeable TMC6\n                      <jats:sup>161\u2013180<\/jats:sup>\n                      peptide competitively displaced CIB1 from TMC6 and augmented hypertrophy in wild-type but not\n                      <jats:italic toggle=\"yes\">Tmc6<\/jats:italic>\n                      knockout cardiomyocytes, indicating a dominant-negative mechanism. Therapeutically, AAV9-cTnT-TMC6 restored TMC6\u2013CIB1 engagement, suppressed calcineurin\/NFAT readouts, and improved function after pressure overload.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>TMC6 is an endogenous brake on pathological hypertrophy that restrains CIB1-calcineurin\/NFAT signaling via endoplasmic reticulum sequestration of CIB1. Restoring full-length TMC6 mitigates pressure-overload remodeling, nominating the TMC6\u2013CIB1 axis as a therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.327680","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T10:00:11Z","timestamp":1772013611000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["TMC6 Is a Novel Therapeutic Target for Pathogenic Cardiac Hypertrophy"],"prefix":"10.1161","volume":"138","author":[{"given":"Hongkun","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (H.W., Z.Y., T.G., D.L., Z.P., J.S., H.F., P.L.)."},{"name":"Institute of Translational Medicine, Zhejiang University, Hangzhou, China (H.W., Z.Y., D.L., Z.P., J.S., F.G., H.F., X.D., Y.C., J.C., P.L.)."},{"name":"Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences (H.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9582-0460","authenticated-orcid":true,"given":"Zongkuai","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (H.W., Z.Y., T.G., D.L., Z.P., J.S., H.F., P.L.)."},{"name":"Institute of Translational Medicine, Zhejiang University, Hangzhou, China (H.W., Z.Y., D.L., Z.P., J.S., F.G., H.F., X.D., Y.C., J.C., P.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1766-4415","authenticated-orcid":true,"given":"Birou","family":"Zhong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China (B.Z., Y.W., X.F., X.Z., Y.-Q.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingyu","family":"Gong","sequence":"additional","affiliation":[{"name":"Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (H.W., Z.Y., T.G., D.L., Z.P., J.S., H.F., P.L.)."},{"name":"Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China (T.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (H.W., Z.Y., T.G., D.L., Z.P., J.S., H.F., P.L.)."},{"name":"Institute of Translational Medicine, Zhejiang University, Hangzhou, 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