Dihydromyricetin attenuates intervertebral disc degeneration by inhibiting NLRP3 inflammasome activation via the Keap1/Nrf2/HO-1 pathway

Abstract

Intervertebral disc degeneration (IVDD) is a highly prevalent chronic degenerative condition that significantly compromises patients' quality of life. Currently employed clinical treatments include surgical intervention and symptom management strategies; however, effective pharmacological strategies are lacking. Dihydromyricetin (DHM) has remarkable anti-inflammatory and antioxidative properties. On the basis of these biological characteristics, we hypothesized that DHM might have therapeutic potential in IVDD through its anti-inflammatory effects. Network pharmacology analysis revealed 130 overlapping targets between DHM and IVDD, with the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway emerging as a crucial regulatory axis. Experimental validation demonstrated that DHM treatment significantly ameliorated LSI-induced disc degeneration, as evidenced by reduced histopathological scores, upregulated expression of extracellular matrix (ECM) proteins. In vitro studies revealed that DHM effectively inhibited IL-1β-induced NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis by decreasing Keap1 expression and activating the Nrf2/HO-1 signaling pathway. Specific silencing of Nrf2 significantly attenuated the protective effects of DHM, further confirming the crucial role of the Keap1/Nrf2/HO-1 pathway in the therapeutic action of DHM. Through integrated network pharmacology analysis and experimental validation, this study demonstrated for the first time that DHM alleviates IVDD by inhibiting Keap1-mediated Nrf2 degradation and activating the Nrf2/HO-1 pathway to suppress NLRP3 inflammasome-mediated pyroptosis. Furthermore, these findings validate the therapeutic potential of natural bioactive compounds in IVDD, providing experimental evidence and a theoretical foundation for the development of novel therapeutic strategies against IVDD.