Zinc Deficiency Exacerbates Cisplatin-Induced Acute Kidney Injury by Impairing Metabolic Adaptation and Antioxidant Defenses.

Abstract

Cisplatin-induced acute kidney injury (Cis-AKI) is a major limitation of chemotherapy and is largely driven by the inability of renal tubular epithelial cells to adapt to metabolic and oxidative stress. Zinc, an essential regulator of cellular stress responses, may influence this vulnerability, but its role in cisplatin nephrotoxicity remains unclear. Here, zinc-normal and zinc-deficient mice were subjected to Cis-AKI. Renal injury was evaluated by histology, serum creatinine (Scr), blood urea nitrogen (BUN), renal zinc levels, and NGAL expression. Transcriptomic analysis was performed to identify pathways altered by zinc deficiency, followed by validation of the AMPK/SIRT1/PGC-1α axis. Oxidative stress and apoptosis were assessed by Nrf2 signaling, antioxidant enzyme expression, SOD activity, MDA levels, TUNEL staining, and Bax/Bcl-2 expression. Zinc deficiency significantly aggravated Cis-AKI, as indicated by increased tubular damage, elevated Scr, BUN, and NGAL levels, and reduced renal zinc content. RNA sequencing revealed suppression of energy metabolism-related programs, accompanied by inhibition of the AMPK/SIRT1/PGC-1α axis, suggesting impaired metabolic adaptation. Zinc deficiency was also associated with reduced Nrf2 signaling, accompanied by decreased expression of antioxidant enzymes and total SOD activity, increased MDA accumulation, and enhanced tubular apoptosis. These findings suggest that zinc deficiency exacerbates Cis-AKI by weakening metabolic adaptation and antioxidant defenses, thereby promoting oxidative stress and apoptosis. Our study identifies zinc as a key regulator of tubular stress adaptation and suggests zinc homeostasis as a potential therapeutic target in cisplatin nephrotoxicity.

Key Findings

• Zinc deficiency significantly worsens cisplatin-induced acute kidney injury (Cis-AKI) by increasing tubular damage and renal dysfunction markers such as serum creatinine, BUN, and NGAL.
• Zinc deficiency suppresses energy metabolism pathways and inhibits the AMPK/SIRT1/PGC-1α axis, indicating impaired metabolic adaptation in renal tubular cells.
• Reduced Nrf2 signaling and antioxidant enzyme expression, along with decreased SOD activity and increased oxidative stress markers, were observed in zinc-deficient mice, leading to enhanced tubular apoptosis.

Clinical Significance

Citation

Zhou Qiyi, Zhu Ziqi, Wan Xiaojuanet al.. Zinc Deficiency Exacerbates Cisplatin-Induced Acute Kidney Injury by Impairing Metabolic Adaptation and Antioxidant Defenses. Chemico-biological interactions. 2026-Oct-03.