Recent understanding of immunometabolic remodeling in pulmonary macrophages: homeostasis, chronic respiratory diseases, and therapeutic targeting

Abstract

Pulmonary macrophages are essential regulators of immune surveillance, tissue homeostasis, and inflammatory responses within the respiratory microenvironment. Emerging evidence indicates that chronic environmental stress and persistent injury induce profound immunometabolic remodeling in these cells, thereby contributing to the development and progression of chronic lung diseases. Under physiological conditions, pulmonary macrophages maintain metabolic homeostasis primarily through oxidative phosphorylation and fatty acid oxidation. However, pathological conditions drive metabolic reprogramming characterized by altered glycolysis, mitochondrial dysfunction, oxidative stress, lipid dysregulation, and disturbed iron homeostasis, leading to persistent inflammation, impaired tissue repair, and progressive remodeling. Recent studies have further highlighted the critical interplay between metabolic pathways, redox signaling, and immune regulation in shaping macrophage phenotypes and functions. Importantly, therapeutic strategies targeting macrophage metabolism and redox balance, together with advances in macrophage-directed drug delivery systems, have emerged as promising approaches for modulating pulmonary inflammation and tissue injury. This review summarizes recent understanding of immunometabolic remodeling in pulmonary macrophages under homeostatic and pathological conditions and discusses emerging therapeutic perspectives targeting macrophage metabolism in chronic respiratory diseases.