DNA damage is one of the key factors that trigger respiratory system-related diseases. In recent years, the crucial role of DNA damage and repair mechanisms in the occurrence and development of lung diseases has been gradually revealed. DNA damage is not only closely related to the onset of lung diseases but also affects the disease process by regulating various biological processes such as cellular senescence, apoptosis, inflammatory responses, and vascular remodeling. This is particularly evident in common lung diseases such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and lung cancer, where the relationship between DNA damage and dysfunction of lung tissue cells has become increasingly prominent. This cellular response engages a coordinated network of DNA repair pathways, notably homologous recombination (HR) and non-homologous end joining (NHEJ) for resolving double-strand breaks, alongside base excision repair (BER) for small oxidative or alkylative lesions and nucleotide excision repair (NER) for bulky helix-distorting adducts, which play a vital role in maintaining genomic stability of lung cells and inhibiting disease progression. Therefore, this article describes the main types of DNA damage, repair pathways, and their mechanisms of action in lung diseases, and explores the research progress of therapeutic strategies targeting DNA damage repair mechanisms in respiratory system diseases. Through a deeper understanding of these mechanisms, new targeted and intervention directions for the treatment of respiratory system diseases may be provided in the future.
The tumor microenvironment (TME) is a critical driver of cancer progression, in which monocytes contribute to tumor development through their phenotypic and functional plasticity. Tumor-derived extracellular vesicles (EVs) are key mediators of intercellular communication within the TME, particularly shaping the immune landscape. Herein, we investigated the effects of MDA-MB-231-derived EVs (MDA-EVs) on the phenotype, molecular profile, and function of human monocytes. MDA-EVs induced a marked expansion of the classical CD14 + + CD16⁻ monocyte subset, accompanied by a reduction in intermediate and non-classical subsets. MDA-EVs also increased CX3CR1 expression across monocyte subsets in a TLR4-dependent manner, while reducing CCR2 expression in classical monocytes, suggesting a shift in migratory signaling. Monocytes exposed to MDA-EVs increased CD206 and arginase-1 expression, HO-1 and TNF-α mRNA levels, and enhanced monocyte migration and invasion. These changes were accompanied by reduced PKM2 Tyr105 phosphorylation, NF-κB activity, and intracellular reactive oxygen species (ROS) levels. Importantly, EV-educated monocytes enhanced the migratory capacity of MDA-MB-231 cells, indicating a tumor-supportive functional effect. Together, these changes support the acquisition of a distinct activation state.
Burn sepsis is a life-threatening complication of severe burns, characterized by pulmonary endothelial injury driving acute lung injury (ALI). Pyroptosis and vascular barrier dysfunction are key pathological in this process; however, their underlying mechanisms remain unclear. Astragalus polysaccharides (APS), a natural anti-inflammatory compound, shows protective potential in burn sepsis, but their specific targets in endothelial injury have yet to be elucidated. A murine model of burn sepsis was established by inducing a full-thickness scald injury followed by intradermal LPS injection. Mice were treated with either low- or high-dose APS. Lung histopathology, vascular leakage, and survival rates were assessed. In vitro stimulation of pulmonary microvascular endothelial cells (PMVECs) was performed using serum collected from burn sepsis mice. Pyroptosis markers, barrier function, and gene expression were evaluated. The regulatory role of Wilms’ tumor 1-associated protein (WTAP) /m⁶A/PFKFB3 axis was explored via gene overexpression, methylated RNA immunoprecipitation (MeRIP), RIP, and mRNA stability assays. Burn sepsis-induced lung injury was alleviated, and the survival rate of burn septic mice was enhanced following APS treatment. APS suppressed ROS production, NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, and pyroptosis, thereby preserving endothelial barrier integrity both in vivo and in vitro. Mechanistically, APS downregulated WTAP expression, which reduced m⁶A modification and the stability of PFKFB3 mRNA via insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3). Furthermore, knockdown of WTAP attenuated pyroptosis and barrier dysfunction in PMVECs, while overexpression of PFKFB3 partially reversed these effects. APS protects against burn sepsis-induced lung injury by modulating the WTAP/m⁶A/PFKFB3 axis, thereby alleviating endothelial pyroptosis and preserving vascular integrity. This mechanism underlies the pulmonary vascular protection conferred by APS in burn sepsis. Astragalus polysaccharides alleviate burn sepsis-induced lung injury by reducing endothelial pyroptosis and preserving endothelial barrier integrity. Astragalus polysaccharides mitigate pulmonary microvascular endothelial cell pyroptosis and barrier dysfunction by downregulating WTAP. WTAP promotes PFKFB3 expression via an m⁶A–IGF2BP3–dependent mechanism. WTAP contributes to pyroptosis and barrier dysfunction by upregulating PFKFB3 in pulmonary microvascular endothelial cells.
Efferocytosis, the clearance of apoptotic cells by phagocytes, is a central process in inflammation resolution, immune tolerance, and tissue repair. Traditionally viewed as a mechanism for silent disposal of dying cells, efferocytosis is now increasingly recognised as a metabolically instructive event that reshapes macrophage function. Apoptotic cells provide not only recognition signals but also metabolite inputs that can be transferred, sensed, or indirectly induced during engulfment and intracellular degradation. In this review, we propose a metabolic relay framework to explain how apoptotic cell-derived and efferocytosis-induced metabolic cues interact through overlapping, context-dependent modules that support pro-resolving macrophage responses. This framework integrates several major metabolic axes, including lipid handling and fatty acid oxidation, arginine–polyamine metabolism, methionine-dependent epigenetic regulation, glycolysis and lactate signalling, and tryptophan–kynurenine metabolism. These pathways support distinct yet interconnected functions, ranging from sustained engulfment capacity and cytoskeletal adaptation to inflammatory gene silencing, repair-associated reprogramming, anti-inflammatory cytokine production, and stabilisation of resolution programmes. We further discuss how the metabolic relay is shaped by tissue-specific microenvironments and how it may fail in chronic inflammation, atherosclerosis, and sterile tissue injury or become pathologically hijacked in the tumour microenvironment. Finally, we highlight therapeutic opportunities and methodological challenges in targeting relay metabolites, metabolic sensors, and macrophage metabolic states. Understanding efferocytosis through a source-resolved and context-dependent metabolic relay framework may provide a unifying framework for linking apoptotic cell clearance to durable inflammation resolution and may guide future strategies for treating inflammatory, cardiovascular, fibrotic, and malignant diseases.
Cystic fibrosis (CF) leads to dehydration of the airway surface liquid layer, resulting in hyperconcentrated mucus, airway obstruction, chronic lung inflammation, bronchiectasis, alveolar space enlargement, compromised mucociliary clearance, and increased susceptibility to bacterial infection. Retinoic acid receptor-related orphan receptor gamma (RORγt) is a transcription factor influencing type 3 immunity, which is associated with immune cell recruitment, lung inflammation, and bacterial clearance. However, the role of RORγt in the pathogenesis of CF has not been determined. Therefore, we hypothesized that the ablation of RORγt modulates the mucoinflammatory phenotype in sodium channel non-voltage-gated 1, β subunit (Scnn1b)-transgenic (Tg+) mice, a mouse model for human cystic fibrosis-like lung disease. To test this hypothesis, we examined the effect of RORγt deletion on the manifestation of mucoinflammatory lung disease in juvenile Tg+ mice. RORγt deletion did not alter the immune cell composition in lung airspace of wild-type (WT) mice. However, RORγt deletion in Tg+ mice resulted in increased immune cell counts in lung airspaces attributable to an increased number of macrophages, neutrophils, and lymphocytes. Also, RORγt deletion in Tg+ mice increased levels of inflammatory mediators, including IL-2, IL-6, IP-10, KC, MIP-1 β , and IL-4 in lung homogenates. Further, the RORγt deficiency resulted in sustained bacterial load in the Tg+ juveniles. The RORγt deletion in both WT and Tg+ mice resulted in increased numbers of tertiary lymphoid structures (TLS), which were characterized by CD3+ T-cells polarized to one side of the structure and CD20+ B-cells organized into distinct follicular aggregates. However, RORγt deletion did not alter mucous cell metaplasia, muco-obstruction, and alveolar space enlargement. Overall, our findings indicate that RORγt deletion exacerbates inflammatory responses and impairs bacterial clearance in CF-like lung disease, thus providing new insights into the roles of RORγt in mucoinflammatory lung diseases.
