Abstract
Diabetic nephropathy (DN) and diabetic osteoporosis (DOP) are frequent and debilitating complications of diabetes mellitus (DM), sharing pathological features such as oxidative stress, inflammation and metabolic dysregulation. However, current therapies rarely address these comorbidities simultaneously. In the present study, a type 2 DM rat model presenting both DN and DOP characteristics was established. Rats were treated with Akebia saponin D (ASD), Semaglutide, or their combination. Renal function, calcium‑phosphate metabolism, bone microarchitecture and mechanical properties were evaluated. Network pharmacology, molecular docking and knockdown validation were employed to elucidate underlying mechanisms. Combination therapy markedly improved glomerular structure, decreased fibrosis, restored trabecular bone volume and strength and corrected metabolic imbalance more effectively than monotherapy. Bioinformatic analysis identified the Klotho‑p53 signaling axis as a potential target. ASD exhibited high binding affinity to Klotho in silico and adeno‑associated virus‑mediated Klotho knockdown reversed therapeutic benefits, confirming its pivotal role. ASD and Semaglutide synergistically alleviated both DN and DOP by modulating the Klotho‑p53 axis, offering a promising strategy for comprehensive DM complication management.