Vitamin D3 facilitates mucosal healing and modulates macrophage polarization in DSS-induced colitis, accompanied by restoration of epithelial Hippo-YAP signaling.

Damage to the epithelial barrier and dysregulated immune responses are core features of ulcerative colitis (UC). Although vitamin D3 (VD3) is widely recognized for immunomodulatory actions, how it contributes to mucosal repair remains incompletely defined. We used a dextran sulfate sodium (DSS)-induced acute colitis model to assess epithelial regeneration, macrophage polarization, and Hippo-Yes-associated protein (YAP) signaling. Mice received 3% DSS in drinking water and were treated with VD3 or vehicle, after which clinical indices, epithelial injury/repair, immune phenotypes, and inflammatory mediators were evaluated. VD3 markedly alleviated colitis severity and partially preserved mucosal architecture. VD3 showed dual protective effects: it reduced epithelial apoptosis and increased the expression of Ki67, zonula occludens-1 (ZO-1), and Claudin-1, indicating enhanced epithelial restitution; in parallel, it shifted macrophage polarization toward an anti-inflammatory M2-like profile and lowered pro-inflammatory mediator levels. At the signaling level, VD3 attenuated DSS-associated Hippo pathway activation and was accompanied by partial normalization of Yes-associated protein 1 (YAP1) phosphorylation status and YAP-related readouts. Collectively, VD3 improved DSS-induced colitis with coordinated enhancement of epithelial repair and immune-resolution features, accompanied by partial restoration of Hippo-YAP signaling, supporting its relevance to mucosal healing.