Mechanisms of Hericium erinaceus polysaccharides on chronic atrophic gastritis: An integrated study of network pharmacology, molecular docking, in vivo experiments, and scRNA-seq.

Abstract

Chronic atrophic gastritis (CAG) is a precancerous lesion that marks a critical stage for preventing gastric cancer progression, yet targeted therapies remain limited. This study evaluated the therapeutic effects and mechanisms of Hericium erinaceus polysaccharide (HEP) in a mouse model of CAG. Comprehensive physicochemical characterization (HPLC, FT-IR, HPGPC, NMR, methylation analysis) identified core structural features of HEP as a highly branched acidic heteropolysaccharide containing five major monosaccharides. Network pharmacology predicted 44 CAG-related targets of HEP, with IKBKB (encoding IKKβ, the catalytic subunit of the IKK complex) prioritized as a main candidate. Molecular docking predicted favorable binding interactions between representative HEP oligosaccharide fragments and IKKβ. In vivo, HEP alleviated gastric mucosal injury, reduced pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and MDA, elevated SOD activity, and suppressed TLR4/MyD88/NF-κB overactivation. Mechanistically, HEP stabilized the NF-κB p65/IκBα interaction, blocking DCA-induced p65 nuclear translocation; loss-of-function assays validated IKKβ as the important functional target. Bulk transcriptomics and reanalysis of a public single-cell RNA-seq dataset revealed regulatory pathways and cell-type-specific expression of HEP candidate targets in the gastric microenvironment, notably genes involved in cytoskeletal remodeling and calcium homeostasis. Collectively, these findings demonstrate that HEP exerts gastroprotective effects against CAG through coordinated anti-inflammatory, antioxidant, and structure-dependent NF-κB inhibitory actions, supporting its potential as a promising natural agent for CAG intervention.