Abstract Rationale Current evidence indicates that obstructive sleep apnea (OSA) is highly prevalent among patients with idiopathic pulmonary fibrosis (IPF), with reported rates ranging from 59% to 88%. Intermittent hypoxemia, a key feature of OSA, has been associated with accelerated lung remodeling and poorer outcomes in patients with interstitial lung disease (ILD). However, the molecular mechanisms linking chronic intermittent hypoxia (CIH)-induced metabolic stress to alveolar epithelial injury remain largely undefined. Mitochondrial dysfunction and metabolic reprogramming are recognized hallmarks shared by OSA and fibrotic lung diseases. Recent studies further suggest that lactate serves as a signaling metabolite capable of remodeling mitochondrial homeostasis through protein lactylation. We therefore hypothesized that CIH-induced lactate accumulation promotes alveolar type II (AT2) cell senescence and fibrogenesis via AARS1-mediated lactylation of the mitochondrial channel protein VDAC1, establishing a self-amplifying metabolic-mitochondrial feedback loop that drives CIH-aggravated pulmonary fibrosis. Methods C57BL/6J mice received intratracheal bleomycin and were subsequently exposed to CIH (5-21% O2 cycles, 8 h/day, 4 weeks). Lung fibrosis was evaluated by histopathology, hydroxyproline assay, and expression of α-SMA, FN1, and Col1a1. MLE-12 cells were subjected to CIH or exogenous lactate, with lactate production inhibited by sodium oxamate and VDAC1 oligomerization blocked by VBIT-12. Cellular senescence, mitochondrial function, and mtDNA release were assessed by immunofluorescence, Western blot, and flow cytometry. Results CIH aggravated bleomycin-induced fibrosis, evidenced by increased collagen deposition, higher Ashcroft scores, and elevated α-SMA and Col1a1 expression. Elevated lactate induced AARS1-dependent VDAC1 lactylation, promoting VDAC1 oligomerization, mitochondrial depolarization, ROS accumulation, and mtDNA leakage. These mitochondrial defects enhanced glycolysis and AARS1 expression, establishing a self-reinforcing feedback loop sustaining lactate-VDAC1 signaling. Blocking lactate production or VDAC1 oligomerization disrupted this loop, reduced AT2 senescence, and alleviated fibrotic remodeling. Conclusions Chronic intermittent hypoxia (CIH) aggravates pulmonary fibrosis by promoting AARS1-mediated lactylation of VDAC1, which enhances its oligomerization, triggers mitochondrial dysfunction, and accelerates alveolar epithelial senescence. This lactylation-dependent feedback loop amplifies lactate metabolism and fibrotic remodeling. Pharmacologic blockade of this metabolic-mitochondrial circuit with Stiripentol, a clinically approved agent with lactate-lowering properties, attenuated CIH-aggravated pulmonary fibrosis in our models and may offer a promising translational strategy for targeting lactate-driven fibrotic progression. This abstract is funded by: None
Wu et al. (Fri,) studied this question.