Hericium erinaceus (lion’s mane) is among the most widely marketed natural product preparations for cognitive health and has a long-documented history of use in East Asian traditional medicine alongside botanical drugs. Its principal bioactive constituents, the cyathane diterpenoids, meroterpenoids and structural polysaccharides, belong to the same natural product chemistry, pharmacokinetic and quality control framework applied to plant-derived phytomedicines. Therefore, H. erinaceus faces the same translational questions of batch consistency, bioavailability and mechanistic definition. Scientific evidence remains complicated by the variations in fruiting body and mycelium biochemistry, extraction procedures and pharmacokinetic data. The current work addresses this gap by compiling natural product chemistry, structure–activity relationships, mechanisms of action, preclinical and human studies, along with analytical quality control of H. erinaceus metabolites. It proposes a matrix-specific quality control approach supported by authentication, biochemical makeup and markers for the starting material (fruiting body/mycelium), in addition to critically evaluating the relevant current studies for strengths and weaknesses. Using bioanalytics, mass spectrometry and metabolomics, we also highlight methodologies for compound quantification and novel biomolecule discovery. By linking chemical standardisation to the clinical evidence base, this review provides a quality assessment framework of the kind required for herbal and other natural product remedies. It also identifies the pharmacokinetic and trial design gaps that currently limit integration of these preparations into evidence-based practice.

Among the various natural products found in Hydrangea species, the bioactive dihydroisocoumarin, phyllodulcin (PD) stands out as a non-caloric, high-intensity sweetener, which is up to 800 times sweeter than sucrose. Additionally, PD possesses medicinal properties and plays plant-specific roles in pathogen resistance and abiotic stress tolerance. However, the biosynthetic pathway of PD in Hydrangea has remained unexplored. To identify intermediates and candidate genes involved in the biosynthesis of PD, we first conducted a screening approach, in which 14 out of 182 different Hydrangea accessions were selected for their contrasting foliar concentrations of PD and closely related hydrangenol (HD). Analysis of phenylpropanoid pathway (PPP) metabolites showed that accessions of H. macrophylla with high PD levels displayed distinct metabolite profiles compared to those with low PD concentrations. Specifically, caffeic acid, ferulic acid, and their derivatives, such as scopolin, scopoletin, esculetin, and fraxetin, were predominant in accessions with low PD concentrations. Conversely, the metabolite levels of phenylalanine, umbelliferone, p-coumaric acid, naringenin, resveratrol, and thunbergiol C (Thn C) were higher in accessions producing more PD. Transcriptome analysis revealed differentially expressed genes involved in phenylpropanoid biosynthesis, flavonoid biosynthesis, and stilbene biosynthesis pathways that are crucial for PD biosynthesis. Moreover, the identification of cyclase and ketoreductase genes, which were upregulated in accessions with high PD, provided further evidence for the biosynthetic pathway leading to PD. Based on metabolite profiling and gene expression data, we propose a hypothetical biosynthetic pathway for PD.