Mechanisms of LPS-induced toxicity in endothelial cells and the protective role of geniposidic acid

Vascular inflammation and oxidative stress are critical pathogenic factors in cardiovascular diseases. Lipopolysaccharide (LPS)-induced endothelial cytotoxicity, driven by oxidative stress and inflammation, remains incompletely understood. This study highlights the molecular mechanisms underlying LPS toxicity, focusing on the ROS/JNK/NLRP3 signaling axis. LPS disrupts mitochondrial function, increases ROS accumulation, activates JNK phosphorylation, and induces NLRP3 inflammasome activation, culminating in Pyroptosis through caspase-1-mediated GSDMD cleavage. Mechanistic studies with the JNK Inhibitor SP600125 confirmed the critical role of the ROS/JNK/NLRP3 pathway in LPS-induced endothelial damage. Additionally, PGC-1α, a key regulator of mitochondrial homeostasis, was identified as a protective factor suppressed by LPS, exacerbating ROS overproduction and inflammasome activation. To validate these findings, geniposidic acid (GPA), a natural antioxidant and anti-inflammatory compound, was employed. GPA effectively reduced ROS levels, inhibited JNK activation, and suppressed Pyroptosis, supporting its utility as a chemical tool to confirm the pivotal role of ROS/JNK/NLRP3 signaling. This study elucidates the intricate interplay between oxidative stress, mitochondrial dysfunction, and Pyroptosis, providing a comprehensive framework for addressing inflammation-driven vascular damage.

JNK; Lipopolysaccharide; NLRP3; Pyroptosis; ROS.