Fenofibrate inhibits TGF-β-induced myofibroblast differentiation and activation in human lung fibroblasts in vitro

Fenofibrate (FF), a peroxisome proliferator-activated receptor-alpha (PPAR-α) agonist and a lipid-lowering agent, can decrease experimental pulmonary fibrosis. However, the mechanisms underlying the antifibrotic effect of FF remain unknown. Hence, this study was conducted to evaluate the effects of FF on transforming growth factor-beta (TGF-β)-induced myofibroblast differentiation and activation in lung fibroblasts. The results showed that FF inhibited alpha-smooth muscle actin (α-SMA) and connective tissue growth factor expression, collagen production, cell motility, SMAD3 phosphorylation and nuclear translocation, and metabolic reprogramming in TGF-β-exposed cells. The inhibitory effect of FF did not decrease with the addition of a PPAR-α antagonist. Moreover, the inhibitory effect given by FF could not be reproduced with the addition of an alternative PPAR-α agonist. FF inhibited mitochondrial respiration. However, rotenone, a complex I inhibitor, did not suppress TGF-β-induced myofibroblast differentiation. Furthermore, the TGF-β-induced nuclear reduction of protein phosphatase, Mg²⁺ /Mn²⁺ -dependent 1A (PPM1A), a SMAD phosphatase, was inhibited by FF. These results showed that FF suppressed TGF-β-induced myofibroblast differentiation and activation independent of PPAR-α activation and impaired mitochondrial respiration. In conclusion, this study provides information on the effects of FF on anti-TGF-β mechanisms.