{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T16:36:30Z","timestamp":1788798990690,"version":"build-2803163510"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100012542","name":"Sichuan Provincial Science and Technology Support Program","doi-asserted-by":"publisher","award":["2025ZNSFSC0616"],"award-info":[{"award-number":["2025ZNSFSC0616"]}],"id":[{"id":"10.13039\/100012542","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012542","name":"Sichuan Provincial Science and Technology Support Program","doi-asserted-by":"publisher","award":["2025ZNSFSC0617"],"award-info":[{"award-number":["2025ZNSFSC0617"]}],"id":[{"id":"10.13039\/100012542","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Phytotherapy Research"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Chronic kidney disease (CKD) is characterized by tubulointerstitial fibrosis and has a high prevalence, with limited clinical treatment options available. Saikosaponin D (SSD) is a major component of the traditional Chinese medicine compound Chaihuang Yishen Granules (CHYS) and exhibits favorable anti\u2013fibrotic effects. However, its role and underlying mechanisms in renal fibrosis remain unclear. To elucidate the protective effects of SSD on CKD\u2010induced renal fibrosis and investigate the underlying mechanism by which SSD alleviates renal fibrosis through regulating hexokinase\u20102 (HK2)\u2010mediated Smad3 activation, CKD models were established using unilateral ureteral obstruction (UUO) and adenine (ADE) induction. Subsequently, SSD was administered via oral gavage as a therapeutic intervention to observe its protective effects against CKD\u2010induced renal fibrosis. Mechanistically, in\u00a0vitro experiments involving HK2 overexpression and knockdown, as well as the use of SIS3 to inhibit Smad3 activation, evaluated the regulatory role of HK2 on glycolysis and Smad3. The results demonstrated that SSD treatment significantly improved the abnormal serum creatinine (CRE) and blood urea nitrogen (BUN) levels in CKD mice, alleviated renal pathological damage, and reduced the expression of fibrosis\u2010related proteins (Col\u2010I, FN, \u03b1\u2010SMA). HK2 was found to promote glycolysis\u2010related enzymes and Smad3 activation. Inhibition of Smad3 activation with 4\u2009\u03bcM SIS3 significantly attenuated TGF\u2010\u03b2\u2010induced fibrosis in tubular cells but had no effect on HK2 expression or glycolysis. Direct suppression of LDHA\u2010mediated lactate production using 25\u2009mM oxamic acid sodium (OX) markedly reduced HK2\u2010induced Smad3 activation and tubular cell fibrosis. This study reveals that SSD significantly alleviates CKD\u2010induced renal fibrosis by inhibiting HK2\u2010mediated Smad3 activation. Lactate, not only as the end product of HK2\u2010driven glycolysis, but also acts as a signaling mediator in HK2\u2010regulated Smad3 activation, facilitating its activation.<\/jats:p>","DOI":"10.1002\/ptr.70187","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T05:30:23Z","timestamp":1767936623000},"page":"812-828","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Saikosaponin D Regulates\n                    <scp>HK2<\/scp>\n                    \u2010Mediated Glycolytic Lactate Signaling to Alleviate\n                    <scp>CKD<\/scp>\n                    \u2010Induced Renal Fibrosis"],"prefix":"10.1002","volume":"40","author":[{"given":"Jian","family":"Jia","sequence":"first","affiliation":[{"name":"Research Center of Integrated Traditional Chinese and Western Medicine, Affiliated Traditional Chinese Medicine Hospital Southwest Medical University  Luzhou 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