Novel Topical Metformin Protects Skin From Radiation Damage By Blocking Fibrosis-related Signatures And Promoting Regeneration While Maintaining Oncologic Safety
Year: 2026
Type: conference-paper
Abstract: PURPOSE: Radiation therapy (RT) is pivotal in breast cancer treatment, however side effects, including radiodermatitis or Radiation-Induced Skin Fibrosis (RISF), cause functional and cosmetic impairments. Current management is primarily supportive with emollients and skincare regimens, often with limited efficacy. Radiation drives fibrosis through oxidative stress, TGF-B, and mTOR signaling. Metformin, a widely used antidiabetic drug, is known to activate AMPK and suppress TGF-B/mTOR pathways, but its radiation mitigation efficacy and oncologic safety in humans is unknown. We conducted comprehensive analyses of efficacy and oncologic safety using our first-of-its-kind human full-thickness skin perfusion model alongside human breast cancer cell lines. METHODS: We implemented a first-of-its-kind Ex vivo human skin model, exposing flaps to 15 Gy irradiation, followed by topical metformin, vehicle cream, or no treatment. Biopsies were analyzed via histology, immunohistochemistry, and next-generation RNA sequencing to assess DNA damage, apoptosis, fibrosis, and pathway activation. In parallel, irradiated and control MCF-7 and MDA-MB-231 breast cancer cell lines were treated with metformin to study effects on cell proliferation (trypan blue and Ki67), viability/cytotoxicity (LIVE/DEAD assay) DNA damage/apoptosis markers (gamma-H2AX, HMGB1, and Caspase 3). RESULTS: Topical metformin markedly reduced epithelial injury, fibrosis progression and DNA damage. Metformin-treated skin showed no epidermal-dermal separation compared to non-treated samples. TUNEL assays confirmed the lowest apoptosis in metformin-treated samples, and gamma-H2AX staining revealed less DNA damage. Gene expression showcased upregulation of DNA repair, antioxidant, ECM remodeling, anti-apoptotic, and proliferative genes, along with downregulation of inflammatory and profibrotic genes. Immunohistochemistry confirmed decreased mTOR, p70S6K, and TGF-B activity and increased AMPK activation. Through RNA-seq, an EPO-led pathway suggested novel epithelial regeneration. In vitro, metformin further enhanced radiation cytotoxicity, reducing tumor proliferation and increasing cell death, confirmed by LIVE/DEAD assays and elevated Caspase 3 and HMGB1 signaling. CONCLUSION: Using a novel human skin model, we demonstrated that topical metformin protects skin from radiation-induced damage and actively promotes tissue regeneration, while simultaneously enhancing the cytotoxic effect of radiation on breast cancer cells. These mechanistic insights, supported by preclinical data in human tissues, establish metformin as a safe, translational therapy for mitigating radiation damage and provide a strong rationale for future clinical trials. *Source: https://ps-rc.org/meeting/Program/2026/MS48.cgi*
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7160623755