Ferroptosis: the potential key roles in idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by recurrent injury to alveolar epithelial cells, epithelial-mesenchymal transition, and fibroblast activation, which leads to excessive deposition of extracellular matrix (ECM) proteins. However, effective preventative and therapeutic interventions are currently lacking. Ferroptosis, a unique form of iron-dependent lipid peroxidation-induced cell death, exhibits distinct morphological, physiological, and biochemical features compared to traditional programmed cell death. Recent studies have revealed a close relationship between iron homeostasis and the pathogenesis of pulmonary interstitial fibrosis. Ferroptosis exacerbates tissue damage and plays a crucial role in regulating tissue repair and the pathological processes involved. It leads to recurrent epithelial injury, where dysregulated epithelial cells undergo epithelial-mesenchymal transition via multiple signaling pathways, resulting in the excessive release of cytokines and growth factors. This dysregulated environment promotes the activation of pulmonary fibroblasts, ultimately culminating in pulmonary fibrosis. This review summarizes the latest advancements in ferroptosis research and its role in the pathogenesis and treatment of IPF, highlighting the significant potential of targeting ferroptosis for IPF management. Importantly, despite the rapid developments in this emerging research field, ferroptosis studies continue to face several challenges and issues. This review also aims to propose solutions to these challenges and discusses key concepts and pressing questions for the future exploration of ferroptosis.

Keywords: Epithelial-mesenchymal transition; Ferroptosis; Fibroblast activation; IPF; Therapeutic targets.

Fig. 1

Iron metabolism, regulation, and ferroptosis. The regulatory mechanisms of iron contribute to the correction of iron metabolism disorders. Any disruption in the processes of iron absorption, transport, storage, or regulation can potentially lead to ferroptosis

Fig. 2

Regulatory pathways of ferroptosis. The figure illustrates the regulatory pathways involved in ferroptosis, which can be broadly categorized into three types. The first category encompasses the three essential components of ferroptosis: abnormal iron metabolism, polyunsaturated fatty acids, and reactive oxygen species. The second category includes the four major defense pathways against ferroptosis: the GPX4-GSH defense pathway, the FSP1-CoQ defense pathway, the DHODH-CoQ defense pathway, and the GCH1-BH4 defense pathway. The third category consists of key genes that regulate ferroptosis, namely NFR2, Tp53, HO-1, and NCOA4

Fig. 3

The regulation of epithelial-mesenchymal transition (EMT) in idiopathic pulmonary fibrosis (IPF) by ferroptosis. TGF-β1 stimulation upregulates the expression of transferrin receptor 1 (TFRC) in human lung fibroblasts, leading to increased intracellular Fe²⁺ levels, which promotes EMT. TGF-β1 also suppresses the GPX4-GSH defense pathway against ferroptosis, while RSL3 can induce both EMT and ferroptosis in IPF by directly inhibiting GPX4. NRF2 translocates to the nucleus, dimerizes with small Maf proteins, and binds to antioxidant response elements (ARE), thereby activating transcription of target genes to maintain cellular homeostasis. Bach1 inhibits the NRF2 signaling pathway by competitively binding to NRF2 dimers, thereby facilitating EMT

Fig. 4

The regulation of fibroblast-myofibroblasts transition (FMT) in idiopathic pulmonary fibrosis (IPF) by ferroptosis. TGF-β1 stimulation upregulates the expression of transferrin receptor 1 (TFRC) in human lung epithelial cells, leading to increased intracellular Fe²⁺ levels, which promotes FMT. Sestrin2 acts as a ferroptosis inhibitor by activating the NRF2 signaling pathway to mitigate oxidative stress, thus inhibiting FMT and alleviating ferroptosis. Downregulation of NRF2 significantly reduces the level of heme oxygenase 1 (HO-1), thereby promoting FMT. The ferroptosis inducer erastin promotes FMT by increasing lipid peroxidation and inhibiting the expression of GPX4