The impact of macrophage metabolism on idiopathic pulmonary fibrosis development and treatment prospectives

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic interstitial pneumonia of unknown etiology, in which macrophages serve as central orchestrators of the pathological microenvironment. During IPF progression, the alveolar macrophage pool undergoes a critical compositional shift: tissue-resident alveolar macrophages (TR-AMs) are progressively depleted and replaced by monocyte-derived alveolar macrophages (Mo-AMs) harboring a distinct pro-fibrotic transcriptional and metabolic identity. These populations differ fundamentally in their baseline metabolic programs, and both undergo further reprogramming within the fibrotic niche that sustains myofibroblast activation and extracellular matrix (ECM) deposition. This review systematically examines how metabolic reprogramming across three principal axes (glucose metabolism, lipid metabolism, and amino acid metabolism) drives pro-fibrotic macrophage polarization in IPF. Within each axis, alterations in metabolic flux and intermediate accumulation converge to reinforce the pro-fibrotic phenotype, promote fibroblast activation, and perpetuate ECM deposition. Importantly, these metabolic alterations differ between TR-AM and Mo-AM subpopulations in ways that reflect their distinct ontogenetic origins and predispose Mo-AMs to preferential pro-fibrotic polarization within the fibrotic microenvironment. Building on this mechanistic framework, we systematically categorize pharmacological modulators targeting these metabolic checkpoints and evaluate the integration of advanced drug delivery systems for precision intervention within the alveolar macrophage niche. This review ultimately proposes a therapeutic strategy that co-targets macrophage ontogenetic origin, polarization state, and metabolic reprogramming as an interconnected axis, offering new perspectives for re-educating macrophages to attenuate fibrotic progression in IPF.