tetano
Editor, Senior Moderator
Can Respir J
. 2026 Jan 11:2026:1049336.
doi: 10.1155/carj/1049336. eCollection 2026. Integrated Mendelian Randomization and Single-Cell RNA Sequencing Analyses Reveal Lactate Metabolism as a Key Pathway in COVID-19-Induced Pulmonary Fibrosis
Xin Zhang[SUP] 1 [/SUP], Liping Jia[SUP] 2 [/SUP], Tuersun Yeziya[SUP] 3 4 [/SUP], Shuyan Yang[SUP] 1 [/SUP], Miaomiao Chen[SUP] 5 [/SUP], Yan Mo[SUP] 6 [/SUP], Xia Tong[SUP] 1 [/SUP], Lanlan Zhang[SUP] 7 [/SUP]
Affiliations
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.
Keywords: COVID-19; Mendelian randomization (MR); SLC16A4; lactate metabolism; pulmonary fibrosis; single-cell RNA sequencing (scRNA).
. 2026 Jan 11:2026:1049336.
doi: 10.1155/carj/1049336. eCollection 2026. Integrated Mendelian Randomization and Single-Cell RNA Sequencing Analyses Reveal Lactate Metabolism as a Key Pathway in COVID-19-Induced Pulmonary Fibrosis
Xin Zhang[SUP] 1 [/SUP], Liping Jia[SUP] 2 [/SUP], Tuersun Yeziya[SUP] 3 4 [/SUP], Shuyan Yang[SUP] 1 [/SUP], Miaomiao Chen[SUP] 5 [/SUP], Yan Mo[SUP] 6 [/SUP], Xia Tong[SUP] 1 [/SUP], Lanlan Zhang[SUP] 7 [/SUP]
Affiliations
- PMID: 41532065
- PMCID: PMC12791023
- DOI: 10.1155/carj/1049336
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.
Keywords: COVID-19; Mendelian randomization (MR); SLC16A4; lactate metabolism; pulmonary fibrosis; single-cell RNA sequencing (scRNA).