Apigenin Mitigates PFOA-Induced Activation of the NLRP3-Pyroptosis Axis and Associated Neurological Damage

Perfluorooctanoic acid (PFOA), a persistent per- and polyfluoroalkyl substance (PFAS), is an environmental contaminant increasingly associated with neurotoxicity, although its precise molecular mechanisms remain poorly understood. Here, we investigated the role of the NF-κB/NLRP3-GSDMD pyroptotic pathway in PFOA-induced neurotoxicity and evaluated the protective potential of apigenin. In in-vitro, N2a neuronal cells were exposed to PFOA, with or without apigenin, and assessed for cell viability, oxidative stress, and inflammasome activation. In in-vivo, mice were administered PFOA with or without apigenin, followed by behavioral, biochemical, and histopathological analyses. PFOA exposure induced significant oxidative stress, reduced neuronal viability, and activated NF-κB signaling, leading to NLRP3 inflammasome activation and GSDMD-mediated pyroptosis. These molecular alterations were associated with neuroinflammation, neuronal injury, demyelination, and cognitive and behavioral deficits in mice. Apigenin treatment markedly attenuated oxidative stress, suppressed NF-κB/NLRP3 signaling, inhibited caspase-1 and GSDMD activation, and improved neurobehavioral outcomes. Collectively, these findings demonstrate that PFOA induces neurotoxicity via activation of the NF-κB/NLRP3-GSDMD pyroptotic axis and identify apigenin as a potential therapeutic agent for mitigating PFAS-associated neurological damage.