Inhibition of DDX5-Mediated G-Quadruplex Unwinding in the β-Catenin 5′-UTR by Magnesium Isoglycyrrhizinate Alleviates Chemotherapy-Induced Intestinal Injury

TL;DR

A compound called magnesium isoglyrrhizinate helps protect the intestines from chemotherapy damage by blocking a protein that disrupts a key signaling molecule.

Contribution

Identifies magnesium isoglycyrrhizinate as a novel DDX5 inhibitor that alleviates chemotherapy-induced intestinal injury by stabilizing β-catenin G-quadruplex structures.

Findings

Magnesium isoglycyrrhizinate (MIG) binds to DDX5 and inhibits its unwinding of β-catenin G-quadruplexes.

DDX5 destabilizes G-quadruplexes in the β-catenin 5′-UTR, reducing β-catenin levels and impairing intestinal barrier function.

MIG restores β-catenin expression and barrier integrity in a dose-dependent manner in vivo.

Abstract

Chemotherapy-induced gastrointestinal toxicity, particularly intestinal barrier disruption and diarrhea, is a major dose-limiting adverse effect with unclear mechanisms. Here, we identify magnesium isoglycyrrhizinate (MIG) as a novel therapeutic agent that ameliorates 5-fluorouracil (5-FU)- and irinotecan-induced intestinal injury by enhancing epithelial barrier integrity. Using MIG as a molecular probe, we revealed a pathogenic mechanism underlying chemotherapy-induced barrier damage. Integrated chemoproteomics (limited proteolysis–mass spectrometry and thermal proteome profiling) analyses revealed direct binding of MIG to the RNA helicase DDX5 (DEAD-box helicase 5), whose expression is markedly increased upon 5-FU-induced injury. Mechanistically, DDX5 destabilizes the G-quadruplex (G4) structure in the CTNNB1 (β-catenin) 5′ untranslated region, suppressing β-catenin production and compromising barrier function. Crucially, MIG acts as a novel DDX5 inhibitor that blocks G4 unwinding, thereby restoring β-catenin expression and barrier integrity in a dose-dependent manner. In vivo, MIG outperforms the canonical DDX5 inhibitor supinoxin in mitigating intestinal damage. Taken together, the results of our study not only establish MIG as a promising therapeutic candidate but also delineate the DDX5/CTNNB1 axis as a targetable pathway for treating chemotherapy-induced barrier dysfunction.

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