Defining the role of mesenchymal Factor Inhibiting HIF (FIH) in pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is the prototypic fibrotic lung disease in which progressive extracellular matrix deposition and remodelling impairs lung function and ultimately causes death. The cause of IPF remains unclear, and no approved treatment for IPF can halt disease progression. Injury to and/or dysfunction of alveolar epithelium are strongly implicated in IPF disease initiation, but what factors determine why fibrosis progresses rather than tissue repair occurs remain poorly understood. We have recently identified that the activity of factor inhibiting HIF (FIH) is reduced in IPF fibroblasts compared to normal healthy lung fibroblasts. Functionally, FIH regulates the expression of LOXL2 and PLOD2 via regulating hypoxia-inducible factor (HIF) activity. This study aims to investigate the hypothesis that in IPF loss of function of FIH is
a key regulator of progressive fibrosis via both HIF-dependent and -independent pathways. Specifically, I will use IPF disease models in conjunction with transcriptomic analysis and molecular cell biology to determine (1) global transcriptomic alteration in FIH-depleted fibroblasts; (2) altered biological processes when FIH is depleted in human lung fibroblasts; (3) determine if the biological alteration is HIF-dependent or not.
Our results showed that FIH depletion in lung fibroblasts led to notable transcriptomic changes, including changes in cell cycle processes, pathways related to hypoxia, cellular metabolism and ECM deposition. Further experiments suggest that FIH depletion impaired mitochondrial function, reducing oxygen consumption rates and ATP production, a process reversed by co-depleting HIF1β, confirming FIH’s impact on bioenergetics via HIF pathways. Meanwhile FIH-depletion downregulated glycolysis but induced cellular senescence in a HIF-independent manner. FIH also reduced TGFβ-induced α-SMA and collagen 1 expression in a HIF-independent manner, suggesting a role in fibroblast-to-myofibroblast transition through non-HIF mechanisms (Figure.1).
In conclusion, FIH plays a critical role in regulating fibroblast metabolism, senescence,and fibroblast-to-myofibroblast transition (FMT) through either HIF-dependent or HIF-independent pathways, offering potential new avenues for therapeutic targeting in fibrotic diseases.

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ORCID for Yihua Wang: orcid.org/0000-0001-5561-0648

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