This study investigates the role of FOXP3+ regulatory T (Treg) cells in Crohn's disease (CD). Using single-cell RNA sequencing (scRNA-seq), the researchers identified five distinct FOXP3+ Treg subpopulations. These subpopulations displayed distinct gene expression profiles, with some showing increased responsiveness to TNFα signaling and impaired suppressive activity. The study found that these proinflammatory Tregs were highly dependent on histone deacetylase (HDAC) activity, as demonstrated by the successful rescue of their suppressive function using the HDAC inhibitor vorinostat. In vitro experiments, including a suppression assay and organoid co-culture systems, validated the findings. The results suggest that targeting these proinflammatory FOXP3+ T cells with vorinostat could be a potential therapeutic approach for CD.This study investigates the role of FOXP3+ regulatory T (Treg) cells in Crohn's disease (CD). Using single-cell RNA sequencing (scRNA-seq), the researchers identified five distinct FOXP3+ Treg subpopulations. These subpopulations displayed distinct gene expression profiles, with some showing increased responsiveness to TNFα signaling and impaired suppressive activity. The study found that these proinflammatory Tregs were highly dependent on histone deacetylase (HDAC) activity, as demonstrated by the successful rescue of their suppressive function using the HDAC inhibitor vorinostat. In vitro experiments, including a suppression assay and organoid co-culture systems, validated the findings. The results suggest that targeting these proinflammatory FOXP3+ T cells with vorinostat could be a potential therapeutic approach for CD.