Caffeic Acid Modulates Protein Disulfide Isomerase-NLRP3 Inflammasome Signaling to Mitigate Inflammation in Acute Pneumonia.

Caffeic acid (CA) is a polyphenol found in various of plants and daily beverages including coffee. It possesses diverse biological effects, including anti-inflammatory properties. Acute pneumonia represents a widespread inflammatory process; however, whether CA can mitigate acute pneumonia and its specific molecular mechanisms remain elusive. Here, we have demonstrated the robust anti-inflammatory effect of CA both in vivo and in vitro. Additionally, protein disulfide isomerase (PDI) was identified as a potential target of CA via activity-based protein profiling strategy coupled with a chemical probe of CA. Moreover, CA was found to covalently bind to PDI through cysteine sites. Subsequent in vivo and in vitro experiments further revealed the inhibition of PDI-mediated NLRP3 inflammasome signaling constituted the specific mechanism through which CA exerts anti-inflammatory effect. In conclusion, our study elucidates the molecular mechanisms underlying the amelioration of acute pneumonia by CA, providing valuable insights into its potential therapeutic application for inflammation-related diseases.