Dehydrodiisoeugenol Alleviates Sodium Palmitate-Induced Mitochondrial Dysfunction and Activates Autophagy in VSMCs via the SIRT1/Nrf2 Axis

A high-fat model utilizing sodium palmitate (PA) to inhibit vascular smooth muscle cells (VSMCs) was established to evaluate to evaluate the effects of Dehydrodiisoeugenol (Deh) treatment. Proliferative viability was assessed using the CCK8 and EdU assays, while cell migration and autophagy were analyzed via wound healing and Transwell assays, well as the MDC assay. Oxidative stress was measured through reactive oxygen species staining, and superoxide dismutase (SOD) activity was assessed spectrophotometrically. The malondialdehyde (MDA) content was determined using a colorimetric assay. Mitochondrial function was evaluated through membrane potential analysis, and apoptosis was detected using flow cytometry. Bioinformatics and molecular docking studies identified key targets of Deh in treating atherosclerosis (AS), exploring its role in activating autophagy and inhibiting apoptosis through modulation of SIRT1. The results of this study demonstrated that PA significantly inhibited autophagy in VSMCs, suppressed cell proliferation and migration, and promoted oxidative stress, mitochondrial dysfunction, and apoptosis. In contrast, treatment with Deh significantly ameliorated the PA-induced functional impairment of VSMCs. Furthermore, bioinformatics and molecular docking revealed a strong interaction between Deh and SIRT1, suggesting that SIRT1 may serve as a direct therapeutic target for treating AS. The results of the rescue experiments confirmed the relationship between Deh and SIRT1. Compared to Deh administration alone, the combination of Deh with SIRT1 overexpression (OE) further enhanced the proliferation, migration and autophagy of VSMCs while inhibiting oxidative stress, mitochondrial dysfunction, and apoptosis. Additionally, the effects of Deh were reversed by small interfering RNA targeting SIRT1 (si-SIRT1). The Western blot results indicated that Deh could regulate the expression of both SIRT1 and Nrf2, suggesting that the SIRT1/Nrf2 pathway may be involved in the Deh's signaling mechanism. Deh activate autophagy inhibited by PA in VSMCs and mitigates PA-induced mitochondrial dysfunction and apoptosis in these cells through the SIRT1/Nrf2 signaling axis.