Calm Under Challenge: Immune Balancing and Stress Quenching Effects of <em>Hericium erinaceus</em> Mycelium in Human Immune Cells

Hericium erinaceus is a medicinal mushroom valued for its neuroprotective, immunomodulatory, and antioxidant activities. While many extracts and bioactive compounds from both mycelium and fruit bodies have been characterized, the mechanisms driving their effects are not fully understood. Here, the transcriptomic and protein-level effects of H. erinaceus mycelium (HDLM) in human peripheral blood mononuclear cells (PBMCs) were investigated, along with antioxidant and iron chelating activity. A commercially available β-glucan-enriched H. erinaceus fruit body extract (FBE) was included in a subset of assays to compare immune-related outcomes between mycelial and fruit body constituents. HDLM activated a wide array of immune- and oxidative stress–related transcripts and pathways, exhibited significant antioxidant activity, and consistently reduced IL-1β, TNF-α, and IL-8 during LPS challenge while maintaining low basal cytokine expression, indicating targeted immunomodulatory activity. FBE almost doubled production of IL-1β when challenged by LPS, whereas HDLM significantly decreased production of this stress mediator. HDLM also demonstrated augmented iron chelating ability when compared to FBE. Depending on tissue source and preparation methods, different H. erinaceus materials may either potentiate or quench stress responses, highlighting the need for bioactivity and safety comparisons across H. erinaceus supplements.