Targeting insulin-like growth factor 1 receptor restricts development and severity of secondary lymphedema in mice

• DOI: 10.1016/j.isci.2025.111948
• Publication Date: 2025-02-04T00:15:38Z
• Authors: Yinan Yuan; Sidney M. Levy; Yong Qiang Yeo; Ramin Shayan; Tara Karnezis; Steven A. Stacker; Marc G. Achen
• Keywords: Cell biology; Science; Q; Pathophysiology

Secondary lymphedema is a debilitating chronic tissue swelling in limb caused by inadequate interstitial fluid drainage due to dysfunctional lymphatic vessels. Pathological enlargement of small lymphatics contributes dysfunction secondary lymphedema, but molecular mechanisms driving this remodeling are unclear. Here, using surgical mouse model and whole-genome microarray, we identified the transcript for insulin-like growth factor binding protein 5 (IGFBP5), negative regulator (IGF) signaling, as most profoundly down-regulated lymphedematous tissue. Notably, IGF signaling via IGF1 receptor (IGF1R) was previously shown promote remodeling. We therefore targeted IGF1R molecule inhibitor linsitinib. Linsitinib restricted during development, likely inhibiting IGF1R-driven vascular endothelial factor-C (VEGF-C) synthesis macrophages. Importantly, linsitinib reduced mice with suggesting therapeutic target disease.