Anti-Neuroinflammatory Naphtho--Pyrones from a Deep-Sea-Derived Fungus3A00562.

Abstract

Inhibition of inflammation and oxidative stress is increasingly recognized as a promising therapeutic strategy for neurodegenerative diseases. In this study, we isolated two new dimeric naphtho--pyrone (a)-fonsecinones B and D (and) and 14 known compounds (-) from the deep-sea-derived fungus3A00562. Their structures were unambiguously determined through integrated physicochemical and spectroscopic analyses. Screening for neuroinflammatory inhibitors using a BV2 microglial cell model identified TMC 256 A1 () as the most potent candidate. Compoundsignificantly suppressed LPS-induced inflammation in BV2 cells without cytotoxicity. It concurrently inhibited LPS-triggered ROS overproduction and neutrophilic infiltration in zebrafish. Subsequent proteomics revealed thattargets NOS2 to modulate Alzheimer's disease (AD)-associated pathways and the KEAP1-NRF2 axis. Molecular docking and dynamics simulations demonstrated thatoccupies the NOS2 heme-binding pocket, thereby preventing dimerization and inhibiting enzymatic activity. Finally,ameliorated locomotor deficits in an AD zebrafish model. Collectively, these findings highlight compoundas a candidate compound for preventing inflammatory and oxidative stress damage during treatment of neurodegenerative diseases, particularly AD.