Targeting α7nAChR-driven brain endothelial pyroptosis mitigates HIV-1 gp120-induced blood-brain barrier breakdown

HIV-1-associated neurocognitive disorder (HAND) persists in over 40% of people with HIV despite effective antiretroviral therapy, underscoring the absence of targeted interventions. Disruption of the blood-brain barrier (BBB) is a hallmark of HAND, yet the mechanisms that link viral proteins to endothelial injury remain insufficiently understood. This study demonstrates that the HIV-1 envelope glycoprotein gp120 induces pyroptosis of brain microvascular endothelial cells (BMECs), thereby compromising BBB integrity. This process is mediated by the α7 nicotinic acetylcholine receptor (α7nAChR)-dependent activation of the ROS/NF-κB/NLRP3 inflammasome axis. Unexpectedly, α7nAChR, typically regarded as anti-inflammatory, exhibits a paradoxical pathogenic role under HIV-1 gp120 exposure, driving inflammatory endothelial cell death rather than protection. Importantly, this detrimental pathway is effectively inhibited by two clinically approved drugs, memantine and metformin, through suppression of α7nAChR. These findings uncover endothelial pyroptosis as a previously unrecognized mechanism of gp120-induced BBB disruption, redefine the functional role of α7nAChR in HAND pathogenesis, and highlight a promising therapeutic strategy through drug repurposing. By revealing a targetable pathway with direct clinical applicability, this work provides mechanistic insights and translational opportunities for preserving BBB function in HIV-associated neuropathology.