Ginsenoside Rg1 Ameliorates LPS ‐Induced Sepsis‐Associated Lung Injury in Mice via VEGFC /D‐ VEGFR3 Signaling‐Mediated Lymphangiogenesis and Lymphatic Remodeling

Sepsis‐induced acute lung injury (ALI) remains challenging to treat, with conventional anti‐inflammatory therapies offering limited efficacy. The lymphatic system is crucial for removing edema and inflammatory mediators, and its impairment can exacerbate lung injury. Ginsenoside Rg1, a bioactive botanical compound, has diverse pharmacological properties, but its ability to modulate lymphangiogenesis in septic ALI is unclear. This study investigated whether Ginsenoside Rg1 can alleviate lipopolysaccharide (LPS)‐induced ALI in mice by promoting lymphangiogenesis via the vascular endothelial growth factor C (VEGFC)/D‐VEGF receptor 3 (VEGFR3) signaling pathway. ALI was induced in C57BL/6 mice by intraperitoneal injection of LPS (10 mg/kg). Mice were treated with Rg1 at low (30 mg/kg) or high (60 mg/kg) doses. Lung injury was assessed by wet‐to‐dry weight ratios, vascular permeability, histopathology, and lymphatic vessel density. Levels of inflammatory cytokines, VEGFC/D, VEGFR3, and downstream signaling molecules were measured by enzyme‐linked immunosorbent assay, western blotting, and qPCR. Ginsenoside Rg1 treatment dose‐dependently reduced pulmonary edema, vascular leakage, and histological damage. It also reversed LPS‐induced decreases in VEGFC/D and increased VEGFR3 expression, resulting in enhanced lymphatic vessel density. Rg1 activated VEGFR3 downstream pathways (ERK/Prox‐1, AKT) and upregulated lymphatic function genes ( CCL21a, ACKR2 ). Ginsenoside Rg1 can attenuate septic ALI by stimulating the VEGFC/D‐VEGFR3 axis to promote functional lymphangiogenesis, thereby facilitating clearance of edema and inflammatory mediators. This mechanism offers a novel therapeutic strategy focused on enhancing clearance rather than only on suppressing inflammation, potentially reducing tissue damage and the side effects associated with conventional treatments.