Armillariella tabescens polysaccharides alleviate ER stress in 5-FU-induced intestinal epithelial injury and mucositis via ARRB1 modulation

Armillariella tabescens polysaccharides (ATPS) were investigated for their protective effects against 5-Fluorouracil (5-FU)-induced intestinal mucositis in IEC-6 cells and a murine model, with a focus on the role of β-arrestin1 (ARRB1) in endoplasmic reticulum stress (ERS) suppression. The study evaluated cell viability, apoptosis, inflammatory cytokine secretion (IL-1β, IL-6, TNF-α), and lactate dehydrogenase (LDH) release in IEC-6 cells, while diarrhea severity, body weight loss, intestinal histopathology, and tight junction protein expression were assessed in C57BL/6 mice. Western blot, immunohistochemistry, and transmission electron microscopy were employed to investigate the underlying mechanisms of ATPS-mediated ERS inhibition. ATPS significantly improved cell survival and proliferation, reduced inflammatory cytokines and apoptosis, alleviated diarrhea severity, mitigated weight loss, and preserved intestinal barrier integrity by upregulating tight junction protein. Mechanistically, ATPS suppressed ERS activation by reducing GRP78, phosphorylated PERK (p-PERK), phosphorylated eIF2α (p-eIF2α), and CHOP expression, effects that were significantly attenuated in ARRB1-knockdown IEC-6 cells and ARRB1⁻/⁻ mice, indicating that ARRB1 is essential for ATPS-mediated ERS suppression and intestinal protection. These findings suggest that ATPS protects against 5-FU-induced intestinal mucositis by modulating ARRB1 and inhibiting ERS, highlighting its potential as a novel therapeutic strategy for chemotherapy-induced intestinal injury.