Beta-Glucan in barley as a natural immunomodulator: mechanisms and therapeutic potential.

Barley (Hordeum vulgare L.) is a major cereal crop recognized for its abundant β-glucan content, a soluble dietary fiber exhibiting significant nutritional and immunomodulatory properties. Structurally composed of mixed-linkage (1→3)(1→4)-β-D-glucopyranosyl units, barley β-glucans possess unique physicochemical attributes underpinning their biological activity. Their biosynthesis is primarily governed by cellulose synthase-like (Csl) genes, notably HvCslF6, while environmental conditions, agronomic practices, and genetic diversity further modulate β-glucan accumulation. β-glucans act as natural immunomodulators, engaging pattern recognition receptors such as Dectin-1, Toll-like receptor 2 (TLR2), and CR3, thereby activating key innate and adaptive immune pathways, including the MyD88 and Syk cascades. This results in enhanced macrophage, dendritic cell, activate natural killer (NK) cells, and T-cell functions, along with modulation of inflammatory and oxidative stress responses. Barley β-glucans also exert antiviral, anti-inflammatory, antioxidant, and metabolic regulatory effects, contributing to the management of chronic conditions including cardiovascular diseases, diabetes, cancer, and inflammatory disorders. Recent advancements in pretreatment (germination, fermentation, ultrasonic-assisted extraction), molecular breeding (QTL mapping, GWAS, MAS), and genome editing (CRISPR/Cas9 targeting Csl genes) have accelerated efforts to optimize β-glucan yield and functionality. Emerging applications extend beyond nutrition to biomedical materials and vaccine adjuvants, driven by β-glucan's ability to induce trained immunity and enhance vaccine responses. Nonetheless, structural heterogeneity and incomplete mechanistic insights pose challenges to clinical translation. This review critically integrates molecular, immunological, and biotechnological perspectives on barley β-glucans, emphasizing the need for multidisciplinary strategies to unlock their full therapeutic and functional potential in advancing human health and sustainable food systems.