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Updated: Mar 1, 2026
Refined Murine Model of Idiopathic Pulmonary Fibrosis
Published on: June 17, 2025
Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy
Yusuke Kurita1, Jun Araya2, Shunsuke Minagawa1
1Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.
Background:
Pirfenidone (PFD) is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis (IPF), but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species (ROS)-mediated platelet-derived growth factor receptor (PDGFR) activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts (LF) was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy.
Methods:
Transforming growth factor-β (TGF-β)-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin (BLM)-induced lung fibrosis model using PARK2 knockout (KO) mice.
Results:
We found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-β. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of lung fibrosis and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD.
Conclusions:
These results suggest that PFD induces PARK2-mediated mitophagy and also inhibits lung fibrosis development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment.
Insights
Pirfenidone (PFD) enhances mitophagy via PARK2, inhibiting myofibroblast differentiation and lung fibrosis, even with insufficient mitophagy, offering insights into IPF treatment.
Area of Science:
- Cell Biology
- Pulmonary Medicine
- Molecular Mechanisms
Background:
- Idiopathic pulmonary fibrosis (IPF) involves myofibroblast accumulation, with autophagy/mitophagy playing a role in pathogenesis.
- Mitophagy influences myofibroblast differentiation by regulating mitochondrial ROS and PDGFR activation.
- Pirfenidone (PFD) is an anti-fibrotic drug for IPF, but its mechanism is not fully understood.
Purpose of the Study:
- To investigate the effect of PFD on autophagy/mitophagy activation in lung fibroblasts (LF).
- To evaluate PFD's anti-fibrotic properties in modulating myofibroblast differentiation during insufficient mitophagy.
- To elucidate PFD's role in PARK2-mediated mitophagy and its impact on lung fibrosis.
Main Methods:
- In vitro models using TGF-β-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF.
- In vivo study using a bleomycin (BLM)-induced lung fibrosis model in PARK2 knockout (KO) mice.
- Assessment of PFD's effect on autophagy/mitophagy, ROS levels, PDGFR-PI3K-Akt signaling, and fibrotic markers.
Main Results:
- PFD induced autophagy/mitophagy activation through enhanced PARK2 expression, partially inhibiting TGF-β-induced myofibroblast differentiation.
- PFD suppressed PARK2 knockdown-induced myofibroblast differentiation by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation.
- In BLM-induced lung fibrosis, PARK2 KO mice showed worsened fibrosis and oxidative stress, which PFD effectively attenuated.
Conclusions:
- PFD induces PARK2-mediated mitophagy, contributing to its anti-fibrotic effects in IPF.
- PFD inhibits lung fibrosis development even in conditions of insufficient mitophagy.
- These findings provide mechanistic insights into PFD's therapeutic action for IPF.
