Lactate exhibits various biological functions, including the mediation of histone and non-histone lactylation to regulate gene transcription, influencing the activity of T lymphocytes, NK cells, and macrophages in immune suppression, activating G protein-coupled receptor 81 for signal transduction, and serving as an energy substrate. The m⁶A modification represents the most prevalent post-transcriptional epigenetic alteration. It is regulated by m⁶A-related regulatory enzymes (including methyltransferases, demethylases, and recognition proteins) that control the transcription, splicing, stability, and translation of downstream target RNAs. Lactate-mediated lactylation at histone H3K18 can modulate downstream target m⁶A modifications by enhancing the transcriptional expression levels of m⁶A-related regulatory enzymes. These enzymes play a crucial role in the progression of diseases such as cancer, fibrosis (in both liver and lung), myocardial ischemia, cerebral hemorrhage, and sepsis. Furthermore, m⁶A-related regulatory enzymes are also subject to lactylation by lactate. In turn, these regulatory enzymes can influence key glycolytic pathway enzymes or modify lactate transporter MCT4 via m⁶A alterations to impact lactate levels and subsequently affect lactylation processes. Graphical abstract 1. Lactate exhibits various biological functions, including the mediation of histone and non-histone lactylation, immune suppression, activating signal transduction, and serving as an energy substrate. 2. Lactate-induced lactylation of histone or non-histone can regulate downstream targets by influencing the transcription and activity of m⁶A-RRE. 3. m⁶A-RRE-mediated modifications can affect key enzymes in the glycolytic pathway or MCT4, impacting lactate levels.

Ferritinophagy, a selective autophagic process mediated by nuclear receptor coactivator 4 (NCOA4), plays a central role in maintaining cellular iron homeostasis by degrading ferritin and releasing stored iron. Under physiological conditions, this process dynamically regulates iron storage and utilization, thereby preventing both iron deficiency and iron overload. However, under pathological conditions such as chronic inflammation, oxidative stress, and harmful environmental exposures, aberrant activation of ferritinophagy leads to excessive ferritin degradation and abnormal expansion of the cytosolic labile iron pool. This, in turn, drives the accumulation of iron-dependent reactive oxygen species and lipid peroxidation, lowering the threshold for ferroptosis initiation, exacerbating tissue injury, and promoting disease progression. Thus, the pathological significance of ferritinophagy lies not only in iron mobilization itself but also in its close coupling with ferroptosis. This “ferritinophagy–ferroptosis axis” has emerged as a key framework for understanding the link between iron dysregulation and disease pathogenesis. In recent years, increasing evidence has shown that this axis is repeatedly activated in various chronic respiratory diseases (CRDs), where it exerts a pivotal role in disease onset and progression. This review systematically summarizes the molecular mechanisms of NCOA4-mediated ferritinophagy and highlights the potential pathogenic role of the ferritinophagy–ferroptosis axis in different CRDs, aiming to provide a theoretical basis for identifying novel therapeutic strategies and intervention targets. Graphical Abstract 1. Ferritinophagy controls intracellular iron release and shapes ferroptosis susceptibility in lung cells. 2. The ferritinophagy–ferroptosis axis shows strong disease- and cell-type specificity across chronic respiratory diseases (CRDs) 3. Targeting iron mobilization pathways may offer new therapeutic strategies for CRDs

The biological processes of pulmonary artery vascular smooth muscle cells (PA‑SMCs) and pulmonary artery endothelial cells in pulmonary arterial hypertension (PAH) are generally abnormal, with increased levels of proliferation and reduced levels of apoptosis. Although microRNAs (miRNAs/miRs) participate in a number of biological processes in a variety of diseases, such as tumors and infections, studies on the association between miRNAs and PAH are limited. In the present study, blood samples were collected from 6 patients with patent ductus arteriosus. The experimental group included 3 patients with severe PAH, while the control group included 3 patients without PAH. Microarray technology was used to detect the presence of any associated miRNAs. Moreover, a rat PAH model was established via left lung resection followed by monocrotaline injection, involving a total of 8 rats in the PAH group and 8 untreated rat in the control group. Reverse transcription‑quantitative PCR was performed to verify the expression levels of the miR‑30 family in the animal model. miR‑30d‑5p mimics and anti‑miR‑30d‑5p were transfected into primary cultured PA‑SMCs. Levels of cytotoxicity and cell apoptosis were examined, and Notch‑3 expression levels were studied using western blotting. The results of the present study demonstrated that miR‑30d‑5p expression was downregulated in both patient blood and animal models of the PAH group compared with control groups. In primary cultured PA‑SMCs, overexpression of miR‑30d‑5p attenuated the platelet‑derived growth factor‑induced toxicity of PA‑SMCs, while knockdown of miR‑30d‑5p resulted in the increased toxicity of PA‑SMCs compared with control group. The apoptosis rate of PA‑SMCs increased with the overexpression of miR‑30d‑5p compared with control group. Moreover, the expression levels of Notch‑3 in the miR‑30d‑5p group were significantly reduced compared with the anti‑miR‑30d‑5p and miR‑NC groups. In total, 10 circulating miRNAs that may be associated with PAH were discovered in the present study. Moreover, the expression of the miR‑30 family was verified in animal models in vivo, and seven miRNAs in this family were discovered that may be associated with PAH. Additionally, miR‑30d‑5p was downregulated in both patients with PAH and animal models compared with control groups. Thus, the results of the present study demonstrated that the regulatory mechanism underlying PA‑SMCs may be via the Notch‑3 signaling pathway.

Bronchopulmonary dysplasia (BPD) is fundamentally characterized by the arrest of lung development and abnormal repair mechanisms, which result in impaired development of the alveoli and microvasculature. Hepatocyte growth factor (HGF), secreted by pulmonary mesenchymal and endothelial cells, plays a pivotal role in the promotion of epithelial and endothelial cell proliferation, branching morphogenesis, angiogenesis, and alveolarization. HGF exerts its beneficial effects on pulmonary vascular development and alveolar simplification primarily through two pivotal pathways: the stimulation of neovascularization, thereby enriching the pulmonary microvascular network, and the inhibition of the epithelial-mesenchymal transition (EMT), which is crucial for maintaining the integrity of the alveolar structure. We discuss HGF and its receptor c-Met, interact with various growth factors throughout the process of lung development and BPD, and form a signaling network with HGF as a hub, which plays the pivotal role in orchestrating and integrating epithelial, endothelial and mesenchymal.

Background: Evidence-based clinical practice guidelines regarding high-flow nasal cannula (HFNC) use for respiratory support in critically ill children are lacking. Therefore, we aimed to determine the risk factors for early HFNC failure to reduce the failure rate and prevent adverse consequences of HFNC failure in children with acute respiratory dysfunction.Methods: Demographic and laboratory data were compared among patients, admitted to the pediatric intensive care unit between January 2017 and December 2018, who were included in a retrospective cohort study. Univariate and multivariate analyses were performed to determine risk factors for eventual entry into the predictive model for early HFNC failure and to perform an external validation study in a prospective observational cohort study from January to February 2019. Further, the association of clinical indices and trends pre- and post-treatment with HFNC treatment success or failure in these patients was dynamically observed.Results: In total, 348 pediatric patients were included, of these 282 (81.0%) were included in the retrospective cohort study; HFNC success was observed in 182 patients (64.5%), HFNC 0–24 h failure in 74 patients (26.2%), and HFNC 24–48 h failure in 26 patients (9.2%). HFNC 24 h failure was significantly associated with the pediatric risk of mortality (PRISM) III score [odds ratio, 1.391; 95% confidence interval (CI): 1.249–1.550], arterial partial pressure of carbon dioxide-to-arterial partial pressure of oxygen (PaCO₂/PaO₂) ratio (odds ratio, 38.397; 95% CI: 6.410–230.013), and respiratory rate-oxygenation (ROX) index (odds ratio, 0.751; 95% CI: 0.616–0.915). The discriminating cutoff point for the new scoring system based on the three risk factors for HFNC 24 h failure was ≥ 2.0 points, with an area under the receiver operating characteristic curve of 0.794 (95% CI, 0.729–0.859, P < 0.001), sensitivity of 68%, and specificity of 79%; similar values were noted on applying the model to the prospective observational cohort comprising 66 patients (AUC = 0.717, 95% CI, 0.675–0.758, sensitivity 83%, specificity 44%, P = 0.009). In this prospective cohort, 11 patients with HFNC failure had an upward trend in PaCO₂/PaO₂ ratio and downward trends in respiratory failure index (P/F ratio) and ROX index; however, opposite directions of change were observed in 55 patients with HFNC success. Furthermore, the fractional changes (FCs) in PaCO₂/PaO₂ ratio, P/F ratio, percutaneous oxygen saturation-to-fraction of inspired oxygen (S/F) ratio, and ROX index at 2 h post-HFNC therapy onset were statistically significant between the two groups (all, P < 0.05).Conclusion: In the pediatric patients with acute respiratory insufficiency, pre-treatment PRISM III score, PaCO₂/PaO₂ ratio, and ROX index were risk factors for HFNC 24 h failure, and the direction and magnitude of changes in the PaCO₂/PaO₂ ratio, P/F ratio, and ROX index before and 2 h after HFNC treatment were warning indicators for HFNC 24 h failure. Further close monitoring should be considered for patients with these conditions.