Objective To determine whether Saikosaponin D (SSD) alleviates renal injury and fibrosis in chronic kidney disease (CKD) models by regulating the long non-coding RNA gm33782 (LncRNA-gm33782) and thereby modulating the glycolysis pathway. Methods A CKD model was established in C57BL/6 mice using unilateral ureteral obstruction (UUO). Thirty mice were randomly assigned to five groups(n=6/group): sham-operated, UUO model, SSD low-dose (30 mg/kg), SSD high-dose (60 mg/kg), and irbesartan positive control (20 mg/kg). After 7 days of oral administration, mice were euthanized and kidneys harvested. Renal pathological injury was assessed using HE, Masson, and Sirius red staining. Fibrosis markers (FN, α-SMA, Col-I) were detected using immunohistochemistry and Western blot. LncRNA-gm33782 expression was quantified by RT-qPCR. Lactate concentration in renal tissue was measured biochemically, and hexokinase 2 (HK2) protein expression (a key glycolytic enzyme) was assessed by Western blot to evaluate associations between LncRNA-gm33782, renal fibrosis and glycolysis.SIn vitro, a fibrosis model was induced in mouse renal tubular epithelial cells (TCMK-1) using transforming growth factor-beta (TGF-β) induction. Knockdown and overexpression of LncRNA-gm33782 were employed to assess its effects on fibrosis markers (FN, Col-I), glycolysis-associated proteins (HK2, pyruvate kinase M2 (PKM2)) and mitochondrial function (cellular oxygen consumption rate, OCR). SSD intervention was then applied under LncRNA-gm33782 overexpression conditions to evaluate its protective effects. Results SSD treatment significantly attenuated renal tissue injury , fibrosis, and lactate accumulation in UUO mice. LncRNA-gm33782 was significantly upregulated in bothSin vivoS(UUO) andSin vitroSfibrosis models (PS< 0.05). SSD intervention effectively reduced LncRNA-gm33782 expression (PS< 0.05).SIn vitro,Sknockdown of LncRNA-gm33782 ameliorated TGF-β-induced cellular fibrosis and suppressed glycolytic activation. Conversely, overexpression of LncRNA-gm33782 exacerbated mitochondrial OCR suppression, fibrosis, and glycolytic activation, and attenuated the protective effects of SSD (P < 0.05). Conclusion SSD alleviates renal fibrosis primarily by targeting and suppressing LncRNA-gm33782 expression. This suppression leads to downregulation of glycolytic activation and restoration of mitochondrial function. LncRNA-gm33782 is a key molecular target mediating the renoprotective effects of SSD.