<p>Podocyte injury from oxidative stress and pyroptosis is closely linked with diabetic kidney disease (DKD). Here, Tetrandrine (TET), derived from tetrandrine root, with anti-inflammatory and antioxidant traits, was studied for its role in podocyte oxidative stress and pyroptosis in DKD. A rat model of DKD was established by high-fat diet feeding combined with intraperitoneal injection of streptozotocin (STZ). Renal function was assessed using urinary albumin to creatinine ratio (UACR), serum creatinine (Scr), and blood urea nitrogen (BUN) levels. Renal pathological morphology was evaluated by hematoxylin-eosin (HE) staining and Masson staining. Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were detected with commercially available kits. DCFH-DA probe was used to detect intracellular ROS levels. Western blot detected pyroptosis-related proteins (TXNIP, NLRP3, GSDMD-N, pro-caspase-1). Inflammatory factors (IL-1β and IL-18) levels were detected by enzyme-linked immunosorbent assay (ELISA). Immunofluorescence staining observed the expression and localization of GSDMD. Administration of TET alleviated renal damage in rats with DKD. In DKD rats, TET suppressed the TXNIP/NLRP3/GSDMD pathway, leading to a decrease in oxidative stress and pyroptosis within the renal tissue. In vitro, by inhibiting the TXNIP/NLRP3/GSDMD signaling pathway, TET mitigated podocyte oxidative stress and pyroptosis triggered by high glucose. Following TXNIP overexpressing, podocyte oxidative stress and pyroptosis that TET initially suppressed were subsequently reversed. Our results reveal that TET represses podocyte oxidative stress and pyroptosis through TXNIP/NLRP3/GSDMD pathway, which provides new therapeutic targets for DKD treatment.</p>