Celastrol in kidney diseases: From therapeutic duality and toxicity to precision renal targeting

Kidney disorders have become a prevalent global public health crisis, accompanied by soaring morbidity and insufficient therapeutic regimens in clinical practice. Celastrol, a biologically active pentacyclic triterpenoid isolated from Tripterygium wilfordii , is well documented to exert powerful anti-inflammatory, antioxidant, and anti-fibrotic bioactivities. A growing body of preclinical data confirms that celastrol yields remarkable renoprotective outcomes in a broad spectrum of renal disease models, encompassing diabetic kidney disease, IgA nephropathy, chronic kidney disease, as well as acute kidney injury. Mechanistically, celastrol alleviates renal inflammatory infiltration, oxidative stress injury, and pathological fibrotic remodeling through the synergistic regulation of pivotal signaling axes, such as PI3K/Akt/NF-κB, p38 MAPK/NF-κB, Nrf2/GPX4, and SIRT1/EZH2/Wnt/β-catenin pathways. However, a narrow therapeutic index and systemic toxicity greatly hinder its clinical translation. To address this, kidney-targeted delivery systems —including nanoparticle-based carriers ( e.g ., liposomes) and microneedle patches—have been developed to increase renal drug accumulation and reduce off-target toxicity. Further efforts should focus on elucidating context-dependent mechanisms, optimizing carrier design, and advancing clinical trials to fully unlock the therapeutic potential of celastrol against kidney diseases.