Qigui didang decoction alleviates renal injury in a diabetic kidney disease model with metabolic memory features: association with ferroptosis and the SIRT1/Nrf2 pathway.

Abstract

OBJECTIVE: This study aims to evaluate the renoprotective effects of QGDD in a DKD model exhibiting metabolic memory features and to explore its potential mechanism involving the regulation of ferroptosis via the SIRT1/Nrf2 signaling pathway. METHODS: A DKD rat model was induced using streptozotocin (STZ). The rats were assigned to the Blank Control Group (C), Model Group (M), Metformin group (Met), and low-, medium-, and high-dose QGDD groups (QGDD-L/M/H). Intervention effects were assessed by monitoring body weight, fasting blood glucose, renal function markers (24-UTP, BUN, Scr, Cys-C, β2-MG), renal histopathology (HE/Masson staining), oxidative stress markers (Fe2+, MDA, GSH, SOD), cell death indicators (TUNEL, ROS), and expression of genes and proteins associated with the SIRT1/Nrf2 pathway (RT-qPCR, Western blot). RESULTS: All QGDD dose groups decreased 24-hour urinary protein excretion and serum levels of BUN, Scr, Cys-C, and β2-MG. The medium-dose QGDD group notably reduced renal Fe2+ and MDA levels, increased GSH and SOD activity, and inhibited ROS accumulation and cellular apoptosis. QGDD activated the SIRT1/Nrf2 pathway, significantly upregulating the mRNA and protein expression of Nrf2, HO-1, and GPX4, while suppressing the accumulation of AGEs and Ferritin. CONCLUSION: QGDD mitigated the persistent elevation of AGEs, a hallmark of metabolic memory in DKD by activating the SIRT1/Nrf2 signaling pathway to inhibit ferroptosis-associated lipid peroxidation and oxidative stress. Its multi-target synergistic effects provide a solid experimental foundation for the use of Chinese herbal formulations in treating DKD. The medium-dose group demonstrated optimal therapeutic efficacy, emphasizing the significance of dose optimization.

Key Findings

• Qigui didang decoction (QGDD) reduced renal injury markers and oxidative stress in a diabetic kidney disease (DKD) rat model.
• QGDD activated the SIRT1/Nrf2 pathway, upregulating Nrf2, HO-1, and GPX4 expression while suppressing AGEs and ferritin accumulation.
• Medium-dose QGDD effectively inhibited ferroptosis-associated lipid peroxidation and cellular apoptosis, improving renal function and oxidative balance.

Clinical Significance

Citation

Wu Yusen, Fan Lifei, You Hongyiet al.. Qigui didang decoction alleviates renal injury in a diabetic kidney disease model with metabolic memory features: association with ferroptosis and the SIRT1/Nrf2 pathway. Pharmaceutical biology. 2026-Dec.