Zinc deficiency exacerbates and supplementation attenuates early-stage obesity-related podocyte injury via Nrf2/HO-1-mediated pyroptosis
- Int Immunopharmacol. 2026 Jul 1:180:116703. doi: 10.1016/j.intimp.2026.116703.
- 1. Department of Nephropathy, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China. Electronic address: [email protected].
- 2. Department of Nephropathy, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China. Electronic address: [email protected].
- 3. Department of Nephropathy, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China. Electronic address: [email protected].
- 4. Department of Nephropathy, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China. Electronic address: [email protected].
- 5. Department of Nephropathy, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China. Electronic address: [email protected].
Zinc deficiency is prevalent in obesity and chronic kidney disease; however, its therapeutic potential and underlying mechanisms in obesity-related glomerulopathy (ORG) remain to be fully elucidated. This study investigated the protective effects of zinc against obesity-induced podocyte injury and Pyroptosis. Analysis of the NHANES (2011-2016) cohort, comprising 4837 adults, revealed an inverse association between BMI and serum zinc levels. Furthermore, zinc deficiency was significantly associated with reduced estimated glomerular filtration rate (EGFR) and increased urinary albumin-to-creatinine ratio (UACR). Using a high-fat diet (HFD)-induced obese mouse model and palmitic acid (PA)-stimulated podocytes, we demonstrated that obesity/lipotoxicity triggers oxidative stress and activates NLRP3 inflammasome-mediated Pyroptosis, as evidenced by increased cleaved-caspase-1 activation, GSDMD cleavage, and elevated IL-1β and IL-18 levels. Zinc supplementation NK252 significantly attenuated proteinuria, podocyte injury, and renal inflammation, accompanied by reduced pyroptosis-related signaling and enhanced Nrf2 activation, including increased nuclear translocation and upregulation of downstream antioxidant targets such as HO-1. Notably, the renoprotective effects of zinc were markedly attenuated in Nrf2-knockdown mice and in podocytes treated with an Nrf2 inhibitor ML385, supporting a functional role of Nrf2 signaling in mediating these effects. Collectively, our findings suggest that zinc supplementation alleviates ORG, at least in part, by modulating the Nrf2/HO-1-NLRP3 inflammasome-associated Pyroptosis signaling in podocytes.