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.
Keywords: Keap1/Nrf2; NF-κB/COX-2; edible mushroom; network pharmacology; neuroinflammation; p-terphenyls.