DsbA-L safeguards T cell mitochondrial redox homeostasis to restrain Th17 differentiation and colitis.

Pathogenic Th17 accumulation drives intestinal inflammation in inflammatory bowel disease (IBD), yet the metabolic mechanisms directing Th17 polarization remain incompletely understood. Here, we identify the mitochondrial matrix protein DsbA-L serves as a critical, cell-intrinsic metabolic checkpoint for Th17 differentiation and intestinal immune homeostasis. In mouse models, dextran sulfate sodium (DSS)-induced colitis downregulated DsbA-L expression and disrupted mitochondrial redox balance in intestinal CD4⁺ T cells. T cell-specific DsbA-L deletion exacerbated colitis and selectively promotes pathogenic Th17 differentiation by increasing mitochondrial reactive oxygen species (mtROS). Pharmacological mtROS scavenging reverses the Th17 bias, establishing mitochondrial redox imbalance as a causal driver of pathogenic polarization. Furthermore, DsbA-L is essential for the therapeutic efficacy of the PPARγ agonist rosiglitazone in colitis. Collectively, our findings position DsbA-L-mediated mitochondrial redox balance as a key regulator of Th17 pathogenicity and intestinal inflammation, offering new conceptual and therapeutic insights for precision intervention in IBD.