Trained immunity in lung injury and repair

Trained immunity refers to a phenomenon in which innate immune cells undergo long-lasting functional adaptation following an initial challenge. This paradigm shift in pulmonary immunology reveals that classical innate cells such as alveolar macrophages and hematopoietic progenitors, as well as structural cells including epithelial and endothelial populations, can acquire memory-like traits through sustained epigenetic and metabolic reprogramming. In the lung, these reprogrammed circuits influence host defense, lung injury, repair, and fibrotic remodeling through mechanisms involving histone H3K4 trimethylation, mTOR-HIF-1α-dependent metabolic shifts, and KLF4-MERTK-driven efferocytosis. Recent studies highlight the dual nature of this response: whereas appropriately tuned training accelerates pathogen clearance and supports epithelial repair, excessive or persistent activation can exacerbate maladaptive inflammation and fibrosis. In this Mini-Review, we summarize advances from 2020 to 2025 on the cellular and molecular regulation of pulmonary trained immunity, its emerging roles in acute respiratory distress syndrome (ARDS) and lung fibrosis, and novel therapeutic approaches that aim to modulate innate immune reprogramming for lung repair.