Caffeic Acid Phenethyl Ester Ameliorates Pulmonary Fibrosis by Inhibiting Epithelial-Mesenchymal Transition via the Sirt1/PGC-1α/Mitochondrial Axis

Pulmonary fibrosis is a severe lung disease characterized by the epithelial-mesenchymal transition (EMT) of alveolar epithelial cells, leading to an increase in fibroblasts or myofibroblasts. Currently, effective therapeutic options for PF remain limited, rendering the inhibition or reversal of EMT a clinically imperative goal. Caffeic acid phenethyl ester (CAPE), a natural flavonoid, exhibits various biological activities, including antioxidant, anti-inflammatory, anticancer, antiviral, and immunomodulatory effects. However, the role of CAPE in EMT-related diseases such as pulmonary fibrosis remains unclear. This study aimed to investigate whether CAPE can target the Sirtuin 1 (Sirt1)/Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) pathway to regulate mitochondrial function, thereby inhibiting EMT and pulmonary fibrosis. Our in vitro and in vivo findings demonstrate that CAPE significantly improves the quantity and function of mitochondria including mitochondrial DNA (mtDNA) content, ATP level, or mitochondrial membrane potential in altered alveolar epithelial cells, increases the ratio of alveolar epithelial to mesenchymal cell markers, and reduces ROS level or collagen expression, ultimately alleviating the degree of fibrosis. These findings establish a robust preclinical foundation for the translational application of CAPE in EMT-related diseases. In conclusion, CAPE may serve as a potential therapeutic agent for pulmonary fibrosis by modulating mitochondrial function through the Sirt1/PGC-1α pathway, underscoring its potential for clinical translation and merit for further investigative efforts in other EMT-associated conditions.