Bioactives of Lion's Mane Medicinal Mushroom Hericium erinaceus (Agaricomycetes) Targeting PPAR Signaling Pathway: An Experimental and In Silico Investigation

<i>Hericium erinaceus</i> is a widely consumed edible mushroom with significant ethnopharmacological value. Nevertheless, the pharmacological understanding of <i>H. erinaceus</i> presenting crucial bioactive compounds, their therapeutic targets, and its benefits across diseases in the form of bioactive-target-disease connectivity is yet to be explored. This study evaluates the antioxidant activity and cytoprotective effects of <i>H. erinaceus</i> extract on V79 fibroblast cells <i>in vitro</i>, to profile its bioactive compounds, and to conduct a network pharmacological analysis to identify key bioactives linked to therapeutic target proteins and diseases. A qualitative analysis identified the existence of tannins, alkaloids, steroids, terpenoids, polysaccharides, and phytosterols. Vibrational infrared spectroscopy confirmed the existence of alkanes, alkenes, alkynes, aromatics, aldehydes, esters, alcohols, aliphatics, and primary amines. Cytoprotective investigation demonstrated that the concentrations (10-25 μg/mL) of the extract preserve 95% cell viability and significant antioxidant properties. Gas chromatography-mass spectrometry analysis of the <i>H. erinaceus</i> extract yielded 49 components. The absorption, distribution, metabolism, excretion, and toxicity (ADMET)-filtered compounds were subjected to target prediction and pathway analysis, which revealed PPARG protein and its signaling pathways were the most significant targets. Further, disease association analysis identified PPARG's links to various diseases, which could benefit from using <i>H. erinaceus</i>. Molecular docking (-6.804 kcal/mol), binding free energy (-42.05 kcal/mol), and dynamic simulations confirmed a strong interaction between PPARG and 2-methyl hexadecanoic acid. These findings underscore the antioxidant and cytoprotective capabilities of <i>H. erinaceus</i> phytochemicals, as well as their potential therapeutic safety and efficacy for further investigation.