Gigantol Ameliorates High-Fat and High-Fructose Diet-Induced Chronic Kidney Disease by Promoting TFEB-Mediated Mitophagy to Suppress Ferroptosis

Abstract Chronic kidney disease (CKD) is a serious public health challenge that closely correlates with unhealthy diets. Gigantol, a naturally active compound derived from the edible plant Dendrobium, has shown potential in renal protection, but its efficacy in treating metabolic dysfunction-related CKD driven by a high-fat and high-fructose diet (HFFD) remains unclear. Here, we found that gigantol restored abnormal renal function and pathological manifestations in HFFD-fed mice. Mechanistically, gigantol suppresses the phosphorylation of TFEB at Ser211 and promotes TFEB nuclear translocation to enhance PINK1/Parkin-mediated mitophagy and suppress ferroptosis. Similar findings were observed in palmitic-acid-induced cell models. Notably, silencing TFEB or blocking mitophagy reversed the effect of gigantol on suppressing ferroptosis and improving renal injury. Overall, this study demonstrates that gigantol alleviates metabolic-dysfunction-related CKD in mice by promoting TFEB-mediated mitophagy to suppress ferroptosis, suggesting that dietary supplementation with Dendrobium or gigantol represents an effective strategy in mitigating CKD, especially subtypes driven by metabolic dysfunction.