Mechanisms of Hericium erinaceus polysaccharides on chronic atrophic gastritis: An integrated study of network pharmacology, molecular docking, in vivo experiments, and scRNA-seq.
Jul 2026· International Journal of Biological Macromolecules· pp.
153556
· 0 citations· 56 references
Medicine
TL;DR
It is demonstrated 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.
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.
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Background Chronic atrophic gastritis (CAG) is a precancerous gastric lesion characterized by persistent inflammatory injury, glandular atrophy, and impairment of gastric mucosal barrier-associated integrity. Huangjin Shuangshen Decoction (HJSS) has shown therapeutic potential in gastritis-related disorders, but its effects on CAG and the underlying mechanism remain unclear. This study investigated whether HJSS alleviates CAG by modulating inflammation-associated barrier dysfunction. Methods CAG was induced in mice by MNNG combined with ranitidine and irregular feeding, followed by treatment with different doses of HJSS, with folic acid as a positive control. Histopathology, gastric function indices, inflammatory mediators, apoptosis-related markers, and barrier-associated molecules were assessed in vivo. MNNG-injured GES-1 cells treated with HJSS-medicated serum were used for in vitro validation. Transcriptomic analysis, network pharmacology, and pharmacological inhibition were integrated to explore the underlying mechanisms. Results HJSS alleviated gastric mucosal atrophy and histopathological injury, improved gastric functional impairment, reduced inflammatory burden, and attenuated apoptosis-associated epithelial injury in experimental CAG. HJSS also promoted the recovery of gastric mucosal barrier-associated molecules, including CFTR, ZO-1, MUC5AC, Occludin, and Claudin-1. Integrated transcriptomic and network pharmacology analyses highlighted an inflammation–barrier framework involving TNF-related signaling and CFTR-associated regulation. In vitro, HJSS mitigated MNNG-induced epithelial injury, whereas CFTR inhibition attenuated the HJSS-associated restoration of CFTR and ZO-1. HJSS was further associated with suppression of TNF/NF-κB signaling and reduced p65 nuclear translocation. Conclusion HJSS alleviates MNNG-induced CAG by attenuating inflammatory injury and promoting the recovery of gastric mucosal barrier-associated molecular features. Its protective effects are associated with suppression of TNF/NF-κB signaling and involvement of CFTR-associated regulation, supporting an inflammation–barrier mechanism underlying the action of HJSS in CAG.
Shuo Zhang, Shuya Zhang, Mengyi Wang et al.· Frontiers in Immunology· 0 citations
