GenX induces neuroinflammatory responses in BV2 microglial cells through mTOR signaling-mediated inhibition of autophagy

Hexafluoropropylene oxide dimer acid (HFPO-DA), commonly known as GenX, can traverse the blood-brain barrier and infiltrate brain tissue, leading to nervous system damage that primarily manifests as neuroinflammation and neuronal apoptosis. Despite these mounting concerns, few studies have comprehensively examined the molecular neurotoxic mechanisms of GenX exposure. In the present study, we examined the neuroinflammatory responses induced by GenX in BV2 microglial cells. Our results revealed that GenX exposure suppressed autophagy in BV2 microglial cells. We further demonstrated that GenX exposure stimulated the PI3K/AKT/mTOR signaling pathway in BV2 microglial cells. Most significantly, GenX exposure enhanced the expression of pro-inflammatory cytokines in BV2 microglial cells. Additionally, we found that rapamycin treatment, which acts as an mTOR inhibitor, reversed the GenX-mediated enhancement of pro-inflammatory cytokines by restoring the inhibited autophagy in BV2 microglial cells. In summary, our findings demonstrate that GenX stimulates pro-inflammatory cytokine production through PI3K/AKT/mTOR-mediated suppression of autophagy. Consequently, therapeutic targeting of the PI3K/AKT/mTOR pathway may serve as a viable treatment strategy for microglia-mediated neuroinflammation.