Chronic kidney disease (CKD) stands as a formidable global health challenge, often advancing to end-stage renal disease (ESRD) with devastating morbidity and mortality. At the central of this progression lies podocyte injury, a critical determinant of glomerular dysfunction. Compound K (CK), a bioactive metabolite derived from ginsenoside, has emerged as a compelling candidate for nephroprotective therapy. Here, we unveil the profound therapeutic potential of CK in a folic acid (FA)-induced CKD mouse model, demonstrating its ability to restore renal function and mitigate podocyte injury. CK exerted its nephroprotective effects by reinforcing inter-podocyte junctions, suppressing aberrant podocyte motility, and preventing podocyte detachment and apoptosis, thereby safeguarding the glomerular filtration barrier. Mechanistically, we identified mitochondrial dysregulation as a key driver of excessive oxidative stress, which is commonly associated with podocyte damage. CK remarkably restored mitochondrial homeostasis by attenuating pathological mitochondrial fission and enhancing mitophagy, thereby rebalancing the delicate mitochondrial network. Intriguingly, CK may disrupt the formation of the Drp1-Bax dimer, a crucial mediator of mitochondrial apoptosis, further averting podocyte loss. Collectively, our findings highlight CK as a potent nephroprotective agent, offering a novel therapeutic avenue for CKD management and redefining possibilities in the battle against progressive renal disease.
