<i>p</i> -Terphenyls from the Fruiting Bodies of <i>Boletopsis leucomelas</i> with Neuroprotective, Anti-Neuroinflammatory, and Antioxidant Activities

<i>Boletopsis leucomelas</i>is a widely consumed edible mushroom with a dark-gray fruiting body. Four new <i>p</i>-terphenyls (<b>1</b>-<b>4</b>, boletamins A-D), one previously reported compound without detailed characterization (<b>5</b>, boletamin E), and seven known compounds (<b>6</b>-<b>12</b>) were isolated from its fruiting body and structurally elucidated via NMR and HRESIMS. Among them, compounds <b>2</b> and <b>3</b> (boletamins B and C) exhibited significant anti-neuroinflammatory, neuroprotective, and antioxidant activities in BV2 microglial and HT22 neuronal cells. Mechanistically, these dual effects were associated with the modulation of the NF-κB/COX-2 and Keap1/Nrf2 signaling pathways, as demonstrated through network pharmacology analysis, molecular docking studies, and experimental verification. Compounds <b>2</b> and <b>3</b> also effectively restored neuronal dysfunction and suppressed the intracellular ROS production in the <i>in vivo</i> <i>Caenorhabditis elegans</i> model induced by <i>Pseudomonas aeruginosa</i> PAO1, without causing toxicity. These findings position boletamins B and C as promising leads for the development of neuroprotective functional foods or nutraceuticals.