Loss of p53 exacerbates autoimmunity by reprogramming propionyl-CoA metabolism and histone modifications in Treg cells.

Metabolic regulation is central to the tumor suppressor function of p53. By analyzing the human patients with autoimmune diseases, we found that p53 expression was significantly reduced in Treg cells, negatively correlating with abnormally elevated BCL-6 levels. p53 loss causes dysregulated immune homeostasis and dampens Treg function in vitro and in vivo. Mechanistically, p53 transcriptionally activates ALDH6A1 expression and propionyl-CoA anabolism to upregulate functional Treg gene expression via histone propionylation. Treg-specific knockout of ALDH6A1 phenocopies the autoimmune responses of p53 deficiency, and propionyl-CoA restoration largely recovers Treg cell function in mice lacking p53 or ALDH6A1. Clinically, impaired p53-ALDH6A1-histone propionylation signaling is observed in patients with autoimmune diseases and correlates with poor efficacy of first-line therapies. Together, these findings reveal a direct connection between propionyl-CoA metabolism and histone modifications, which is governed by p53 and is crucial for Treg cell function and immune tolerance suppression.