Synephrine Inhibits Oxidative Stress and H₂O₂-Induced Premature Senescence

Synephrine, a protoalkaloid found in Citrus aurantium (CA) peels, exerts lipolytic, anti-inflammatory, and vasoconstrictive effects; however, its antioxidant activity remains unclear. In this study, electron spin resonance spectroscopy revealed that synephrine scavenged both hydroxyl and superoxide anion radicals. Several external stimuli, such as H₂O₂, X-rays, and ultraviolet (UV) radiation, cause stress-induced premature senescence (SIPS). As oxidative stress induces SIPS, we hypothesized that synephrine, an antioxidant, would suppress H₂O₂-induced premature senescence in WI-38 cells. Synephrine significantly decreased the reactive oxygen species levels induced by H₂O₂, thereby reducing lipid peroxidation, and oxidative DNA damage and preventing SIPS. Additionally, synephrine inhibited mitochondrial dysfunction in H₂O₂-treated WI-38 cells. The expression levels of p53, p21, and p16^-INK4A, which are involved in the induction of cell cycle arrest in SIPS, were significantly lower in synephrine-treated cells than in untreated cells. Our results indicate that synephrine inhibits H₂O₂-induced oxidative stress and mitochondrial dysfunction, suppressing premature senescence by inhibiting activation of the p53-p21 and p16^-INK4A-pRB pathways.