Increasing local adipogenic signaling through cutaneous delivery of rosiglitazone decreases fibrosis in secondary lymphedema

BACKGROUND: Secondary lymphedema is a common, debilitating consequence of oncologic surgery that leads to irreversible skin and subcutaneous fibrosis. No topical anti-fibrotic therapy currently exists. We previously showed that systemic rosiglitazone, a peroxisome proliferator-activated receptor-γ (PPARγ) agonist, promotes adipogenesis and reduces fibrosis in experimental lymphedema, but systemic toxicity limits its use. METHODS: A murine tail model of secondary lymphedema was used to compare systemic and topical rosiglitazone. scRNA-seq data was initially used to justify interrogation of rosiglitazone as a therapeutic compound. A novel topical formulation was developed and tested in murine skin ex vivo. Outcomes included fibrosis, adipogenesis, and systemic toxicity, evaluated by histology, immunofluorescence, and bone marrow adiposity. RESULTS: Systemic rosiglitazone reduced fibrosis, increased anti-fibrotic adiponectin expression, and reduced infiltration of CD4⁺ T cells into lymphedematous tissue. Topical rosiglitazone reproduced these anti-fibrotic and pro-adipogenic effects locally, increased epidermal and dermal adiponectin expression, achieved full dermal penetration, and avoided systemic effects such as bone marrow adipogenesis. CONCLUSIONS: Topical rosiglitazone is a novel, safe, and clinically translatable strategy to mitigate cutaneous fibrosis in secondary lymphedema. By repurposing an FDA-approved drug with localized delivery, this approach may offer reconstructive surgeons the first noninvasive pharmacologic option to address this irreversible complication. CLINICAL RELEVANCE STATEMENT: Fibrosis is the most challenging aspect of lymphedema, as it permanently alters tissue quality and limits patient quality of life. Our topical rosiglitazone formulation reduces fibrosis and enhances adipose tissue, offering a novel strategy to improve tissue quality and surgical outcomes.