Organelle Crosstalk and Metabolic Reprogramming in Idiopathic Pulmonary Fibrosis: Mechanisms and Therapeutic Implications.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease of unknown cause, marked by excessive deposition of extracellular matrix (ECM) components such as collagen. This pathological accumulation results in progressive destruction of the lung architecture and ultimately leads to respiratory failure. Growing evidence indicates that dysfunction across multiple cell types is an important driver of IPF. Nevertheless, its underlying pathobiology remains incompletely understood. The normal integrity of organelles is critical for cellular function, and in different IPF lung cells, such as alveolar epithelial cells (AECs), fibroblasts, and macrophages, we found dysfunctional development of key organelles and metabolic reprogramming changes driving malignant progression of pulmonary fibrosis. This review summarizes the contributions of key organelles-mitochondria, the endoplasmic reticulum, lysosomes, and peroxisomes-and functional changes in metabolic reprogramming during IPF progression. We further clarify the core mechanisms of how inter-organelle network disruptions drive fibrosis, with the goal of identifying critical organelle nodes to disrupt pathogenic metabolic reprogramming and ultimately provide a rationale for developing new treatments.