Integrated Mendelian Randomization and Single‐Cell RNA Sequencing Analyses Reveal Lactate Metabolism as a Key Pathway in COVID‐19‐Induced Pulmonary Fibrosis

Background The COVID‐19 pandemic has led to a variety of long‐term complications, with COVID‐19‐induced idiopathic pulmonary fibrosis (IPF) becoming a major concern. However, the underlying mechanisms, effective therapeutic strategies, and long‐term prognosis of COVID‐19‐related pulmonary fibrosis remain unclear. Methods This study utilized Mendelian randomization (MR) analysis and single‐cell RNA sequencing (scRNA‐seq) to systematically investigate the molecular mechanisms underlying COVID‐19‐induced pulmonary fibrosis. MR analysis was conducted to assess causal relationships, while scRNA‐seq provided detailed insights into the cellular and molecular processes involved in fibrosis. Results MR analysis revealed a significant association between COVID‐19 infection and the development of IPF (OR = 1.15, 95% CI = 1.05–1.25, p = 0.001), whereas the reverse causality—IPF increasing the risk of COVID‐19 infection—was not significant. Mediation analysis identified lactate metabolism as a crucial intermediary pathway in COVID‐19‐induced IPF (OR = 1.30, 95% CI = 1.09–1.55, p = 0.003). scRNA‐seq confirmed the central role of lactate metabolism in pulmonary fibrosis, particularly in lung epithelial cells. The key lactate transport gene, SLC16A4, was found to play a significant role in the progression of fibrosis. Additionally, cellular interaction analysis revealed that lung epithelial cells interacted with fibroblasts via the PDGFC–PDGFRA signaling axis, promoting fibrosis. Conclusion This study uncovers a critical mechanism by which COVID‐19 promotes pulmonary fibrosis through the regulation of lactate metabolism in lung epithelial cells, with SLC16A4 playing a pivotal role. These findings highlight the potential of targeting this metabolic pathway as a therapeutic approach for pulmonary fibrosis, offering new directions for future antifibrotic treatment strategies.