Protocatechuic Acid Alleviates Inflammation and Oxidative Stress in Acute Respiratory Distress Syndrome by Promoting Unconventional Prefoldin RPB5 Interactor 1-Mediated Mitophagy.

Summary

Using LPS-induced cellular and murine models of ARDS, the authors show that protocatechuic acid suppresses inflammatory cytokines, oxidative stress, and apoptosis while improving histology. Mechanistically, PCA targets CBX4 to recruit GCN5 and upregulate URI1, thereby enhancing mitochondrial biogenesis and mitophagy; knockdown of CBX4 or URI1 abrogates these benefits.

Key Findings

• PCA (300 μM in HPMECs; 20–30 mg/kg in mice) reduced proinflammatory cytokines, oxidative stress, and apoptosis, and improved alveolar septal thickening.
• CBX4 was identified as a direct PCA target; PCA recruited GCN5 to the URI1 promoter to enhance transcription.
• LPS lowered CBX4/URI1 levels; PCA restored them, and CBX4 or URI1 knockdown abolished PCA’s anti-inflammatory and pro-mitophagy effects.

Clinical Implications

While preclinical, the CBX4–URI1–mitophagy pathway could guide development of mitochondrial-directed adjuncts for ARDS. Biomarker work to measure pathway activation in patients may stratify candidates for future trials.

Limitations

• LPS models may not capture the heterogeneity of human ARDS etiologies
• Sample sizes and dose–exposure relationships for clinical translation were not detailed; no human validation

Future Directions

Quantify CBX4/URI1 pathway activation in human ARDS, assess pharmacokinetics/pharmacodynamics of PCA analogs, and test efficacy in diverse injury models and large animals prior to early-phase trials.