Topical delivery of a PPARγ agonist enables adipogenic repair of irradiated skin.

Radiation therapy is a cornerstone of cancer treatment, yet it frequently results in radiation-induced tissue injury (RITI), causing long-term morbidity such as chronic wounds, impaired mobility, joint dysfunction, and wound healing complications following oncologic resection. RITI is characterized by fibrosis, diminished adipogenesis, and reduced vascularity, ultimately compromising reconstructive outcomes. Current topical treatments are limited to moisturizers and corticosteroids, the latter of which may delay wound healing. Surgical interventions-including adipose grafting and complex tissue transfer-remain the mainstay of treatment but are associated with high morbidity. There is a critical need for a low-risk, accessible strategy for primary prevention of RITI. We developed a novel topical formulation of the peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone to enhance regenerative healing in irradiated skin. In murine models, topical rosiglitazone increased dermal adipocyte presence, restored regenerative capacity in irradiated skin by reprogramming mesenchymal progenitors, and reduced fibrotic collagen deposition. These changes were associated with accelerated wound healing in irradiated fields. Our findings demonstrate that local PPARγ activation promotes adipogenic and vascular regeneration while limiting fibrosis, thereby improving tissue resilience to radiation injury. This non-invasive, easily administered topical therapy offers a promising strategy for preventing RITI in the nearly one million patients who undergo radiation therapy annually in the United States.