Protocatechuic Acid Alleviates Inflammation and Oxidative Stress in Acute Respiratory Distress Syndrome by Promoting Unconventional Prefoldin <scp>RPB5</scp> Interactor 1‐Mediated Mitophagy

Protocatechuic acid (PCA) is a type of polyphenol with diverse biological activities, including antioxidant and anti-inflammatory properties. This study aimed to explore the function of PCA in acute respiratory distress syndrome (ARDS) and delve into its functional mechanism. Lipopolysaccharides were applied to stimulate human pulmonary microvascular endothelial cells (HPMECs) or C57BL/6 mice to generate ARDS models in vitro and in vivo. PCA treatment (300 μM for cells and 20 or 30 mg/kg for mice) reduced proinflammatory cytokine production and oxidative stress in HPMECs or mouse models, and it reduced cell apoptosis while alleviating alveolar septum thickening. Chromobox 4 (CBX4) was identified as a target protein of PCA, and it was found to activate the transcription of unconventional prefoldin RPB5 interactor 1 (URI1) by recruiting histone acetyltransferase general control nondepressible 5 (GCN5) to its promoter region. CBX4 and URI1 levels were reduced by LPS but restored by PCA. Knockdown of either CBX4 or URI1 negated the ameliorating effects of PCA on LPS-induced inflammation and oxidative stress and diminished the promoting roles of PCA in promoting mitochondrial biogenesis and mitophagy. This study suggests that PCA holds promise in alleviating inflammation and oxidative stress in ARDS by promoting CBX4/URI1-mediated mitophagy.