Puerarin alleviates sciatic nerve injury in diabetic peripheral neuropathy rat via HSP90AA1

Diabetic peripheral neuropathy (DPN) is one of the most prevalent complications of Diabetes. Puerarin, a natural isoflavone glycoside extracted from Pueraria lobata, has been proven effective for DPN, while the mechanisms underlying its therapeutic effects remain elusive. This study aimed to elucidate the neuroprotective mechanisms of puerarin on the sciatic nerve in DPN. A streptozotocin-induced DPN model was established in Sprague-Dawley rats to assess the therapeutic efficacy of puerarin. The findings revealed that puerarin intervention remarkably ameliorated mechanical allodynia and abnormal thermal responses in DPN rats, as evidenced by Von Frey and hot-plate tests. Meanwhile, sciatic motor nerve conduction velocity (MNCV) was markedly enhanced in DPN rats, as evidenced by the electrophysiological detection results. Histopathological examination showed that puerarin restored the structural integrity of injured myelin sheaths. Network pharmacology analysis predicted that puerarin might modulate apoptosis via the PI3K/AKT signaling pathway by interacting with ten core targets, including HSP90AA1, AKT1, IL6, ESR1, TLR4, mTOR, NFKB1, MAPK1, CDK1 and NFE2L2. Molecular docking confirmed a strong binding affinity between puerarin and HSP90AA1. Furthermore, electron microscopy, TUNEL staining, and Western blot analyses corroborated that puerarin restored autophagy and reduced the number of apoptotic cells in sciatic nerve of DPN rats. Mechanistically, puerarin upregulated HSP90AA1 expression and enhanced AKT phosphorylation. Collectively, these findings demonstrate that puerarin alleviates sciatic nerve injury in DPN by promoting protective autophagy and suppressing aberrant pathological apoptosis simultaneously through the HSP90AA1/AKT axis, offering a potential therapeutic strategy for DPN.