researcher Affiliated BenQ Hosp., Nanjing Med. Univ., United States
Disclosure(s):
Haiyang Jiang, PhD: No financial relationships to disclose
Introduction/Rationale: Intestinal barrier failure and impaired epithelial metabolism typify IBD. We identify a splicing-dependent program of gasdermin B (GSDMB) in intestinal epithelium and an injury signature—fumarate hydratase (FH) loss with fumarate build-up—during GSDMB-driven death. Distinct isoforms differentially affect barrier integrity and metabolism. We test a therapeutic concept: fumarate-mediated succination of GSDMB to block pyroptosis and promote repair.
Methods: We profiled programmed cell death and GSDMB in Crohn’s IECs by molecular assays and scRNA-seq. Epithelial functions were interrogated in Villin-Cre knock-in mice expressing human GSDMB or rs2305480, and in tamoxifen-inducible epithelial FH knockouts under DSS colitis. Mechanistic work used bulk RNA-seq, human/murine organoids, mass spectrometry to map succination, and cysteine mutagenesis. Dimethyl fumarate (DMF) and 4-octyl fumarate (4-OF) were delivered systemically or via a xanthan-gum platform for sustained intraluminal release.
Results: Inflamed IECs upregulated GSDMB, with isoforms 3 and 1 predominant. GSDMB activation coincided with FH reduction, fumarate accumulation, and mitochondrial injury. Epithelial FH deletion worsened DSS colitis and permeability. DMF/4-OF suppressed GSDMB cleavage by succinating key cysteines—isoform 3: C49/C241/C283; isoform 1: C49/C228/C270—independent of splicing context. Both agents mitigated colitis in GSDMB and rs2305480 knock-in mice, improving clinical scores and epithelial repair. Xanthan-gum delivery extended intestinal exposure and enhanced barrier restoration.
Conclusion: GSDMB links epithelial metabolic stress (FH loss, fumarate excess) to pyroptotic injury. Fumarate-driven succination blocks GSDMB cleavage, preserves barrier function, and attenuates colitis. Optimized fumarate donors with sustained intraluminal delivery represent a tractable therapeutic strategy for intestinal inflammation.
