Emerging Therapeutic Potential of Fisetin for Nephrotoxicity, Kidney Injury, and Nephropathy: A Systematic Review.

Introduction/objective: Kidney diseases cause high morbidity and mortality worldwide. This study investigated the mechanistic effects of Fisetin (FIS) on nephrotoxicity, kidney injury, and nephropathy induced by drugs, toxic chemicals, diabetes, lupus, diet, ureteral obstruction, and ischemic situations.

Methods: To identify pertinent articles published before Oct 1, 2024, a comprehensive electronic search was performed across several databases, including MEDLINE/PubMed, Embase, Cochrane Library, Web of Science, and Scopus. After establishing clear inclusion and exclusion criteria, studies that met the research objectives were selected. Data were extracted and analyzed, documenting study characteristics, methodologies, and biological mechanisms.

Results: Antioxidant benefits were evident with increased levels of endogenous antioxidant enzymes and NQO1, alongside reduced oxidative stress markers such as 8-OHdG and MDA. Enhanced mitochondrial function, including improved respiration, ATP synthesis, and antioxidant capacity, further supported cellular resilience. Anti-inflammatory effects were marked by reduced pro-inflammatory cytokines, macrophage and neutrophil infiltration, and inhibited pathways like NF-κB and MAPK. Anti-apoptotic actions included decreased levels of pro-apoptotic proteins. FIS also reduced fibrotic markers and pathways such as TGF-β/SMAD, mitigating excessive ECM buildup. Additionally, modulation of metabolic pathways was observed, including decreased glucose and lipid profiles and improved insulin sensitivity. Kidney function and structural integrity were preserved with reduced levels of nephrotoxic agents.

Conclusion: Preclinical studies revealed that FIS demonstrates promising protective effects against kidney toxicity, renal injury, diabetes, and lupus-induced nephropathy. However, more clinical studies are needed in this field to determine effective and safe doses.