Bioactive Compounds of Sideritis Species in Inflammation, Neuroprotection and Cardiometabolic Health: A Review.

Sideritis species (Lamiaceae), the aromatic mountain teas of the Mediterranean and Balkans, accumulate a phytochemically rich array of bioactive compounds-phenylethanoid glycosides (notably verbascoside), flavonoid aglycones and glycosides, phenolic acids, and terpenoids-whose pharmacological relevance is increasingly defined at the molecular level. This review synthesizes current evidence on the molecular mechanisms through which these constituents act in human health and disease, integrating in vitro, in vivo, in silico, and clinical data. Anti-inflammatory activity is attributed to modulation of the NF-κB and NLRP3 inflammasome pathways; direct verbascoside binding to both targets has been demonstrated in vitro by microscale thermophoresis (nanomolar-to-micromolar Kd), with suppression of TNF-α and IL-1β observed in cell-based and animal models. Neuroprotective effects are proposed to operate through amyloid-β clearance via ADAM10 upregulation and enhanced microglial phagocytosis in transgenic mouse models, together with in vitro triple monoamine (serotonin, noradrenaline, dopamine) reuptake inhibition, and are supported at the functional level by small randomized clinical trials reporting cognitive and anxiolytic benefits. Antioxidant and cytoprotective actions reflect radical scavenging, metal chelation, and restoration of SOD/CAT/GSH with attenuation of lipid peroxidation, underpinning documented hepatoprotective and gastroprotective outcomes. Preliminary cardiometabolic findings from small clinical trials include cholesterol modulation and sex-dependent effects on insulin sensitivity that remain to be confirmed in larger, adequately powered cohorts. We further evaluate structure-activity relationships, species- and tissue-level chemical variability, and green extraction strategies relevant to standardized bioactivity-preserving preparations. Critical gaps-in vivo validation of antiproliferative effects documented only in cell-based and in silico studies so far, systematic toxicological assessment, and bioavailability characterization-are identified to guide translation. Collectively, Sideritis-derived phytochemicals, exemplified by S. scardica, represent a mechanistically coherent group of plant bioactives with defined molecular targets in inflammatory, neurodegenerative, and metabolic disorders.