{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:49:01Z","timestamp":1791521341193,"version":"4.3.4"},"reference-count":46,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82474427"],"award-info":[{"award-number":["82474427"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Astragaloside IV (AS\u2010IV) has demonstrated efficacy in ameliorating proteinuria and attenuating renal tubular damage in preclinical diabetic nephropathy (DN) models. Despite these multi\u2010target benefits, the molecular mechanisms underlying its podocyte\u2010protective effects remain largely uncharacterized, particularly its potential epigenetic regulatory capacity within glomerular cells. This study aimed to test the hypothesis that AS\u2010IV protects against DN by activating the deacetylase sirtuin 6 (SIRT6). Specifically, AS\u2010IV activates SIRT6, which deacetylates Histone H3 at Lysine 9 (H3K9) at the\n                    <jats:italic>Notch1<\/jats:italic>\n                    promoter, thereby suppressing\n                    <jats:italic>Notch1<\/jats:italic>\n                    expression. This\u00a0suppression is expected to enhance autophagy and reduce apoptosis, ultimately repairing renal filtration barrier injury. A murine model of DN was induced with\u00a0streptozotocin and a high\u2010fat diet. To simulate diabetic damage, MPC\u20105 podocytes were subjected to high glucose (HG, 33\u2009mM). Renal function metrics were extensively evaluated, and glomerular histopathological and ultrastructural changes were assessed by hematoxylin and eosin staining and electron microscopy. Subsequently, downstream mechanisms involving podocyte autophagy and apoptosis were investigated by immunofluorescence staining and Western blotting. To confirm that SIRT6 directly regulates\n                    <jats:italic>Notch1<\/jats:italic>\n                    transcription via histone deacetylation, our study utilized chromatin immunoprecipitation (ChIP). Our results showed that AS\u2010IV treatment alleviated renal biochemical and pathological abnormalities in DN mice and attenuated podocyte injury, evidenced by restoring nephrin and podocin expression and reducing glomerular basement membrane thickness (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01). Functionally, AS\u2010IV treatment reversed HG\u2010induced podocyte apoptosis and autophagy dysfunction (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01). Mechanistically, AS\u2010IV was confirmed to directly bind to SIRT6 (Kd\u2009=\u20090.164\u2009\u03bcM). ChIP assays demonstrated increased SIRT6 occupancy and consequently reduced H3K9ac enrichment at the\n                    <jats:italic>Notch1<\/jats:italic>\n                    promoter (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01). In summary, AS\u2010IV may ameliorate DN by activating the SIRT6\/H3K9ac\/\n                    <jats:italic>Notch1<\/jats:italic>\n                    epigenetic axis, providing a strong molecular basis for AS\u2010IV as a promising therapeutic agent against DN.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70472","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:53:53Z","timestamp":1791518033000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Astragaloside\n                    <scp>IV<\/scp>\n                    Restores Autophagy and Inhibits Apoptosis for Podocyte Protection in Diabetic Nephropathy by Inhibiting Notch1 Signaling via\n                    <scp>SIRT6<\/scp>\n                    \u2010Mediated Deacetylation"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6264-3587","authenticated-orcid":false,"given":"Qiyu","family":"Yue","sequence":"first","affiliation":[{"name":"The First School of Clinical Medicine Nanjing University of Chinese Medicine  Nanjing China"},{"name":"Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine  Nanjing China"},{"name":"Jiangsu University Key Laboratory of Tonifying Kidney and Anti\u2010Senescence  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Yong","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine  Nanjing China"},{"name":"Jiangsu University Key Laboratory of Tonifying Kidney and Anti\u2010Senescence  Nanjing 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Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubai","family":"Xue","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine Nanjing University of Chinese Medicine  Nanjing China"},{"name":"Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Deng","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine Nanjing University of Chinese Medicine  Nanjing China"},{"name":"Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine  Nanjing 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