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

Boletopsis leucomelasis a widely consumed edible mushroom with a dark-gray fruiting body. Four new p-terphenyls (1–4, boletamins A–D), one previously reported compound without detailed characterization (5, boletamin E), and seven known compounds (6–12) were isolated from its fruiting body and structurally elucidated via NMR and HRESIMS. Among them, compounds 2 and 3 (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 2 and 3 also effectively restored neuronal dysfunction and suppressed the intracellular ROS production in the in vivo Caenorhabditis elegans model induced by Pseudomonas aeruginosa PAO1, without causing toxicity. These findings position boletamins B and C as promising leads for the development of neuroprotective functional foods or nutraceuticals.