Targeting NF-κB in diabetic nephropathy: exploring the therapeutic potential of phytoconstituents

The growing epidemic of diabetes mellitus and its associated complications presents a major global health challenge. Diabetic nephropathy (DN) is a critical microvascular complication of diabetes, accounts for approximately one-third of all related cases worldwide and frequently progresses to end-stage renal disease (ESRD) and premature mortality. Extensive experimental evidence underscores the pivotal role of chronic inflammation driven by the activation of the nuclear transcription factor NF-κB in the pathogenesis of DN. Triggered by various factors including hyperglycemia, NF-κB activation leads to the expression of numerous pro-inflammatory cytokines, chemokines and cell adhesion molecules, resulting in the pathological hallmarks of DN: podocyte injury, excessive extracellular matrix accumulation, glomerulosclerosis, epithelial-mesenchymal transition, renal tubular atrophy and increased proteinuria. Consequently, NF-κB emerges as a promising therapeutic target for DN. Naturally occurring phytoconstituents, as inhibitors of the NF-κB pathway and are gaining significant attention due to their lower toxicity, enhanced safety, greater efficacy and cost-effectiveness. This review summarizes the role of NF-κB in the pathophysiology of DN and examines recent research on medicinal plants and phytoconstituents that target the NF-κB signaling pathway in both in vitro and in vivo and in silico models. Furthermore, we elucidate their mechanisms of action and evaluate their potential as effective therapeutic agents for mitigating DN-related inflammation and complications. This provides a theoretical framework for the development of novel anti-nephropathic drugs that may overcome the limitations of current medications.