Metformin eliminates lymphedema in mice by alleviating inflammation and fibrosis: implications for human therapy.

Abstract

Secondary lymphedema is a chronic, disabling disease impacting over 50% of patients with cancer and lacking effective pharmacological treatment even for early- to mid-disease stages. Metformin reportedly exerts anti-inflammatory and anti-fibrotic effects and is safe, with minimal side effects; We investigated the role of metformin in lymphedema mouse models and examined underlying molecular mechanisms. Male C57BL/6 mice (6-8-week-old; n=15/group) received metformin (300 mg/kg/day) by gavage on day 3 after lymphedema surgery; saline and sham groups were administered the same volume of saline. Hindlimb circumference and tail volume were monitored every two days. On day 28, samples were collected for histological assessment, western blotting, and reverse transcription-quantitative PCR analysis of inflammation, fibrosis, and AMPK expression. AMPK activity was assayed in patients with secondary lymphedema (ISL II) and controls following strict inclusion criteria. Compared with the saline group, the metformin group exhibited hindlimb circumference and tail volume reduced by 469.70% and 305.18%, respectively. on day 28. Dermal thickness was reduced by 38.27% and 72.57% in the hindlimbs and tail, respectively. Metformin decreased CD4+ T cell infiltration by 19.73% and expression levels of interleukin (IL)-4, IL-13, IL-17, and transforming growth factor-β1. Additionally, it lowered collagen I deposition by 33.18%. Compared with the saline group, the number of lymphatic vessels increased by 229.96% in the metformin group. Both the saline group mice and patients with lymphedema showed reduced AMPK activity, while metformin increased p-AMPK expression by 106.12%. Metformin alleviated inflammation and fibrosis and increased lymphangiogenesis in lymphedema mouse models by activating AMPK signaling.