Urtica dioica L. Phytochemistry, Green Extraction Techniques, Molecular Mechanisms, and Gene Expression Modulation: A Comprehensive Review.

Urtica dioica L. (stinging nettle) is a perennial herb with a long ethnomedicinal history and diverse pharmacological potential. This comprehensive review consolidates current knowledge on its phytochemistry, extraction technologies, bioactivities, and molecular mechanisms. However, recent reviews have generally addressed these aspects separately, and an integrated assessment linking green extraction technologies and phytochemical profiles to molecular mechanisms and gene expression modulation is still lacking. U. dioica contains abundant polyphenols (rutin, quercetin, kaempferol, and chlorogenic acid), sterols (β-sitosterol and stigmasterol), vitamins, carotenoids, and the antiviral lectin Urtica dioica agglutinin (UDA). Advances in green extraction technologies, such as ultrasound-assisted extraction, microwave-assisted extraction (MAE), pressurized liquid extraction, and natural deep eutectic solvent (NADES)-based systems, have significantly improved yield, purity, and environmental sustainability compared to conventional maceration and Soxhlet methods. Comprehensive chromatographic and spectroscopic profiling (HPLC, GC-MS, FTIR, NMR, and LC-MS/MS) has established detailed chemical fingerprints linking bioactive constituents to antioxidant, anti-inflammatory, antimicrobial, and antiviral properties. Mechanistic studies reveal that U. dioica exerts its therapeutic effects through modulation of oxidative stress, inhibition of the NF-κB and COX-2 pathways, enhancement of endogenous antioxidant enzymes, and regulation of apoptotic gene expression. Moreover, NADES-MAE extracts demonstrate potential as sustainable, high-efficacy formulations for nutraceutical and cosmetic applications. Despite extensive preclinical evidence, clinical standardization and dosage optimization remain major challenges. This review underscores U. dioica as a multifunctional medicinal plant with significant promise for next-generation phytotherapeutics and molecular nutrition.