Causal Relationship Between Methotrexate and Chronic Obstructive Pulmonary Disease: A Study Based on Network Toxicology and Mendelian Randomization

Introduction: Previous studies have shown that methotrexate (MTX) may have potential effects on chronic obstructive pulmonary disease (COPD), but the specific causal relationship remains unclear. Objective: This research intends to investigate whether a potential causal association exists between MTX usage and the risk of developing COPD. Methods: To systematically explore the potential association between MTX and the occurrence of COPD, this study adopted a multi-dimensional research strategy: on the one hand, the network toxicology method was used to predict the relevant action targets and metabolic pathways of MTX; on the other hand, the Mendelian randomization (MR) analysis method was applied to conduct research at the macro-epidemiological level. Results: Network toxicology analysis showed that MTX can affect the onset of COPD through multiple pathways and metabolic routes, and has strong binding energy with proteins encoded by HIF1A, EP300, NFKB1, PPARG, ABL1, STAT1, HDAC1, NFE2L2 , and MAPK1 . Meanwhile, MR analysis showed a significant positive correlation between MTX and COPD. Conclusion: This study suggests that there is a certain association between the use of MTX and the increased risk of COPD, providing new ideas for subsequent in - depth research.