Lycopene AttenuatesDEHP-Induced Cerebral Injury bySuppressing cGAS-STING-Mediated Microglial Activation

Abstract Di(2-ethylhexyl) phthalate (DEHP) is a widespread environmental pollutant with neurotoxicity, while lycopene (LYC) is a neuroprotective dietary carotenoid. This study investigated whether LYC alleviates DEHP-induced brain injury by regulating microglial activation and cGAS-STING signaling. ICR mice were treated with LYC (5 mg/kg) and/or DEHP (500 mg/kg) for 28 days, with results validated in BV2 cells. In vivo, DEHP exposure impaired spatial learning and memory, triggered neuronal degeneration, microglial activation and mitochondrial dysfunction, increased 2′3′-cGAMP production, and activated cGAS-STING signaling. LYC supplementation markedly reversed these changes. Network toxicology, molecular docking, and molecular dynamics suggested cGAS as a potential LYC target. In vitro, MEHP-induced M1 polarization was attenuated by LYC, and cGAS silencing verified the pathway’s critical role in LYC’s protection. These findings indicate that LYC alleviates DEHP-induced neural damage by maintaining mitochondrial homeostasis and inhibiting cGAS-STING-mediated microglial activation, providing a potential nutritional strategy for preventing brain damage caused by environmental pollutants.