Neuroprotective Terpenoids Derived from <i>Hericium erinaceus</i> Fruiting Bodies: Isolation, Structural Elucidation, and Mechanistic Insights.

Abstract

<i>Hericium erinaceus</i>, a medicinal macrofungus, is renowned for its potential neuroprotective benefits. Here, we isolated and characterized secondary metabolites from <i>H. erinaceus</i> fruiting bodies and explored their neuroprotective effects and primary mechanisms of action. A novel terpenoid (4) and four known compounds (<b>1</b>, <b>2</b>, <b>3</b>, and <b>5</b>) were identified. Their chemical structures were determined using nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), and x-ray diffraction (XRD). Bioactivity screening using PC12 cells indicated that (3R,4R)-4-acetyl-3,4-dihydro-6,8-dihydroxy-3-methoxy-5-methyl-1H-2-benzopyran (3) and the terpenoid, (1R,4S,8aS)-1,4-dihydroxy-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carbaldehyde (4), demonstrated protective properties against hydrogen peroxide (H₂O₂)-induced damage. Transcriptomics, network pharmacology, and molecular docking showed that compound <b>4</b> counteracted H₂O₂-induced oxidative stress and inflammation by substantially attenuating pro-inflammatory cytokine (IL-1β, IL-6) expression, downregulating pro-oxidant factors (Aoc3, Dusp3), and decreasing reactive oxygen species levels, while boosting superoxide dismutase activity. Compound <b>4</b> exerted neuroprotective effects via the NF-κB pathway. <i>H. erinaceus</i> represents a valuable natural reservoir of bioactive compounds for treating and preventing neurodegenerative diseases.