Pan-peroxisome proliferator-activated receptor agonist IVA337 alleviates secondary lymphedema via inhibiting TGFβ/SMAD2/3 signaling pathway.

Lymphedema is a chronic disease characterized by impaired lymph drainage and accumulation of protein-rich interstitial fluid, which progresses to develop irreversible fibrosis. Despite its substantial clinical burden, effective pharmacological therapies that improve lymphatic function and prevent disease progression remain lacking. Given the prominent inflammatory and fibrotic responses associated with lymphedema, we investigated the therapeutic potential of IVA337 (lanifibranor), a pan-peroxisome proliferator-activated receptor (PPAR) agonist that activates PPARα, PPARβ/δ, and PPARγ, key regulators of lipid metabolism, inflammation, and fibrosis. Here, we evaluated the therapeutic efficacy of IVA337 during the early stage of surgery-induced secondary lymphedema in mice and investigated the underlying mechanisms. IVA337 administration alleviates lymphedema progression, improves lymphatic drainage, reduces dermal thickness, and resolves lymphatic vessel dilation. Mechanistically, IVA337 suppresses TGFβ/SMAD2/3 signaling pathway, reduces immune cells infiltration, and improves lymphatic vessels integrity. In human dermal lymphatic endothelial cells (HDLECs), IVA337 attenuates TGFβ induced SMAD2/3 phosphorylation and preserves the expression of cell junction Claudin5, reduces VE-Cadherin-stained cell-cell gaps. Collectively, our findings demonstrate that IVA337 protects against early-stage lymphedema by suppressing TGFβ/SMAD2/3 signaling and limiting inflammatory and fibrotic and lymphatic endothelial dysfunction. These findings identify pan-PPAR activation as a promising pharmacological strategy to preserve lymphatic function during the early phase of lymphedema and potentially prevent progressive tissue fibrosis.