2658 - Targeting the Mucus Barrier: A Novel Radioprotective Strategy via Abelmoschus manihot Polysaccharide-Mediated Alleviation of Endoplasmic Reticulum Stress

Purpose/Objective(s):

The mucus barrier plays a critical role in intestinal defense, yet its therapeutic potential remains largely untapped in radiation oncology.This study identifies, for the first time, the natural compound Abelmoschus manihot polysaccharide (AMP) as a potent radioprotector that specifically preserves mucus secretion by mitigating goblet cell endoplasmic reticulum (ER) stress—a previously unrecognized mechanism in radiation-induced intestinal injury (RIII).

Materials/Methods:

We employed a murine model of 14 Gy whole abdominal irradiation with or without oral AMP prophylaxis. Comprehensive in vivo assessments included survival, histomorphometry, mucus layer quantitation, epithelial integrity, inflammation, and stem cell dynamics. Mechanistic studies utilized primary mouse goblet cells and intestinal organoids, combined with the ER stress inducer thapsigargin, to establish causality. ER stress was evaluated through biomarkers (GRP78, CHOP), ultrastructural imaging, and functional rescue experiments.

Results:

AMP pretreatment significantly improved survival (30% increase, p<0.01) and clinical outcomes in irradiated mice. Crucially, AMP uniquely preserved the colonic mucus layer thickness and goblet cell numbers, which correlated with maintained expression of the core mucin MUC2. At the mechanistic level, AMP was shown to directly suppress radiation-induced ER stress in goblet cells, preventing ER dilatation and vacuolization, and downregulating GRP78 and CHOP. This ER stress mitigation was functionally essential: AMP-enhanced epithelial integrity, stem cell proliferation (Lgr5?, OLFM4?), and lineage differentiation were all abolished upon co-treatment with thapsigargin. Similarly, in intestinal organoids, AMP’s pro-survival and pro-budding effects were entirely reversed by ER stress induction, confirming the centrality of this pathway.

Conclusion:

We establish a novel radioprotective paradigm: pharmacological preservation of the mucus barrier through alleviation of goblet cell ER stress. AMP exemplifies this strategy, demonstrating that targeted support of mucus-producing cells is both feasible and therapeutically effective against RIII. These findings position AMP as a first-in-class, barrier-focused radioprotectant with direct translational potential for improving the therapeutic index of abdominal-pelvic radiotherapy.