Vanin-pantethine metabolic axis shapes dendritic cell function and affects inflammatory disorder progression

Aberrant activation of dendritic cells (DCs) is intricately associated with inflammatory diseases, rendering DCs an appealing therapeutic target. Metabolites are emerging as crucial regulators of DCs, yet therapeutic strategies targeting DC metabolism for inflammatory diseases remain underexplored. Our study identifies the Vanin-pantethine-cholesterol axis as a key metabolic pathway that governs DC activation-a classical APC function. We found that Vanin is upregulated in activated DCs from autoimmune patients and mice; DC-specific Vanin deficiency significantly alleviates psoriasiform inflammation in mice. Mechanistically, Vanin hydrolyzes pantethine, leading to cholesterol and lipid raft accumulation on the cell membrane and promoting DC hyperactivation. Pantethine supplementation or pharmacologically induced Vanin inhibition reduces cholesterol overload, impedes DC activation, and mitigates psoriasiform inflammation. Notably, pantethine or RR6 treatment impairs activation of patient-derived DCs, and our investigator-initiated trial shows that pantethine combination therapy relieves clinical symptoms in psoriasis patients. Collectively, these findings establish the Vanin-pantethine-cholesterol axis as a key modulator of APC function, offering a promising metabolic approach for inflammatory diseases.