Structural repair of the intestinal epithelium is strongly correlated with disease remission in inflammatory bowel disease (IBD); however, ulcer healing is not addressed by existing therapies. To address this need, this study reports the use of a small molecule prolyl hydroxylase (PHD) inhibitor (DPCA) to upregulate hypoxia‐inducible factor one‐alpha (HIF‐1α) and induce mammalian regeneration. Sustained delivery of DPCA is achieved through subcutaneous injections of a supramolecular hydrogel, formed through the self‐assembly of PEG‐DPCA conjugates. Pre‐treatment of mice with PEG‐DPCA is shown to protect mice from epithelial erosion and symptoms of dextran sodium sulfate (DSS)‐induced colitis. Surprisingly, a single subcutaneous dose of PEG‐DPCA, administered after disease onset, leads to accelerated weight gain and complete restoration of healthy tissue architecture in colitic mice. Rapid DPCA‐induced restoration of the intestinal barrier is likely orchestrated by increased expression of HIF‐1α and associated targets leading to an epithelial‐to‐mesenchymal transition. Further investigation of DPCA as a potential adjunctive or stand‐alone restorative treatment to combat active IBD is warranted.
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