Exploration of upstream and downstream mechanisms of the TAGLN2 gene in pulmonary arterial hypertension

This study systematically explored the upstream and downstream mechanisms of the TAGLN2 gene regulated by DNA methylation and its succinylation modification in the pathogenesis of pulmonary arterial hypertension (PAH) by integrating Mendelian randomization and mediation analysis. The results showed that DNA methylation sites cg13892570 and cg16107628 significantly downregulated TAGLN2 expression (β = -0.53 and -0.61, P < .05), indirectly reducing the risk of PAH. The mediating effects of TAGLN2 accounted for 86.46% and 97.65% of the total effect, respectively. Further analysis indicated that TAGLN2 might promote PAH progression through immune and metabolic pathways: on the one hand, by activating HLA DR+ monocytes (mediation proportion 6.15%), it exacerbated pulmonary vascular inflammatory responses; on the other hand, by increasing the levels of eicosadienoic acid (mediation proportion 5.21%) and cysteinyl dipeptide (mediation proportion 3.15%), it induced oxidative stress and lipid metabolism disorders. Bioinformatics validation suggested that TAGLN2 was significantly overexpressed in the lung tissues of PAH patients (P < .05), and its succinylation modification might enhance the pro-PAH effect by altering protein stability and function. This study first proposed the "DNA methylation-TAGLN2 succinylation-immune/metabolic" regulatory axis, providing new ideas and potential targets for the epigenetic mechanism and precise treatment of PAH. However, the relevant conclusions still need to be further verified by subsequent experiments.