Recombinant human Thymosin β4 ameliorates experimental colitis and intestinal fibrosis through suppression of mineralocorticoid receptor signaling.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by epithelial barrier disruption, persistent mucosal inflammation, and progressive intestinal fibrosis, for which effective therapeutic options remain limited. Thymosin β4 (Tβ4) is a highly conserved endogenous peptide with established roles in tissue repair and immune regulation, but its contribution to IBD pathogenesis has not been fully elucidated. Here, we found that TMSB4X, the gene encoding Tβ4, was downregulated in colonic tissues of IBD patients. To investigate its functional significance, we generated Tmsb4x-deficient mice and demonstrated that loss of endogenous Tβ4 markedly increased susceptibility to dextran sulfate sodium (DSS)-induced colitis. Conversely, oral administration of recombinant human Tβ4 (rhTβ4) significantly improved survival, alleviated body weight loss, reduced epithelial injury, and suppressed inflammatory cytokine production in both prophylactic and therapeutic colitis models. Furthermore, rhTβ4 attenuated intestinal fibrosis, as evidenced by reduced expression of fibrosis-associated markers and decreased collagen I deposition. Transcriptomic analysis revealed that rhTβ4 partially restored DSS-induced gene dysregulation and suppressed mineralocorticoid receptor (MR, NR3C2) signaling, a pathway further supported by reporter assays and downstream target gene analyses. Collectively, these findings identify Tβ4 as an endogenous protective factor against intestinal inflammation and fibrosis and suggest that pharmacological restoration of Tβ4 activity may represent a promising therapeutic strategy for IBD through modulation of mineralocorticoid receptor signaling.