{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T10:00:43Z","timestamp":1790071243389,"version":"4.0.1"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Heart failure remains a leading cause of mortality globally, driven by persistent mitochondrial dysfunction and maladaptive cardiac hypertrophy. Although impaired autophagic flux contributes to cardiac deterioration, the precise molecular mechanisms are still unclear. The ubiquitin-proteasome system serves as a critical regulator linking protein ubiquitination to autophagic flux and mitochondrial homeostasis. Asb2 (ankyrin repeat-containing protein with suppressor of cytokine signaling box 2), a muscle-specific E3 ubiquitin ligase essential for embryonic cardiogenesis, is uncharacterized in adult cardiac homeostasis and disease pathogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Male mice with inducible cardiomyocyte-specific Asb2 knockout were generated to investigate Asb2\u2019s role in cardiac remodeling. Adeno-associated virus 9\u2013mediated cardiomyocyte-specific Asb2 overexpression and KIF11 (kinesin family member 11) downregulation were used in transverse aortic constriction\u2013induced hypertrophy and aging models. RNA sequencing, metabolite profiling, and mass spectrometry were used to assess the molecular mechanism by which Asb2 regulates cardiac metabolism and hypertrophy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Asb2\u03b2 expression was significantly reduced in multiple forms of human cardiomyopathy and in hypertrophic murine hearts. Inducible Asb2 deletion in adult male mice led to the spontaneous development of cardiac hypertrophy and heart failure, accompanied by progressive accumulation of dysfunctional mitochondria and metabolic dysregulation. Mechanistically, Asb2 deficiency impaired ubiquitin-mediated degradation of KIF11, causing aberrant peripheral lysosomal redistribution and disrupting autophagosome-lysosome fusion, which resulted in impaired late-stage autophagic flux and metabolic disturbances. Notably, therapeutic restoration of Asb2 expression via adeno-associated virus 9-mediated delivery attenuated pressure overload\u2013induced and age-related cardiac hypertrophy and heart failure. Moreover, both genetic and pharmacological inhibition of KIF11 effectively restored autophagic flux and mitochondrial homeostasis, thereby reversing pathological cardiac remodeling in Asb2-deficient hearts and transverse aortic constriction\u2013induced cardiac dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Asb2 is a novel regulator of mitochondrial quality control in cardiomyocytes via KIF11-mediated lysosomal redistribution. Targeting the Asb2-KIF11 axis may be a promising strategy for improving mitochondrial homeostasis and cardiomyocyte function in chronic heart failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.126.080625","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T09:01:39Z","timestamp":1790067699000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Asb2-KIF11 Axis Protects Against Heart Failure by Restoring Lysosomal Distribution and Mitochondrial Homeostasis"],"prefix":"10.1161","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2576-1224","authenticated-orcid":true,"given":"Yicheng","family":"Lv","sequence":"first","affiliation":[{"name":"State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences (Y.L., Z.S., Z.D., S.L., H.W., D.K.), Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5819-815X","authenticated-orcid":true,"given":"Zhao","family":"Sha","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences (Y.L., Z.S., Z.D., S.L., H.W., D.K.), Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7842-9892","authenticated-orcid":true,"given":"Shi","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, China (S.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Duan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences (Y.L., Z.S., Z.D., S.L., H.W., D.K.), Shanghai Jiao Tong 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