Integrated Mendelian Randomization and Single-Cell RNA Sequencing Analyses Reveal Lactate Metabolism as a Key Pathway...

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.

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.

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.

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.