Clinical discovery of anti-CYP2E1 autoantibodies and preclinical efficacy of a CYP2E1 inhibitor in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by aberrant and persistent immune responses against self-antigens. However, the mechanisms of autoantibody production and the specific self-antigens in RA are not fully understood. CYP2E1 has been identified as a novel inflammatory target. It also exhibits immunogenicity and participates in autoimmune pathogenesis. Here, we explored the role of CYP2E1 in RA. In this study, we found that anti-CYP2E1 autoantibodies and CYP2E1 are elevated in RA and are closely related to inflammation and immunity. Cyp2e1 knockout protected RA rats against joint damage. Preclinical investigations further demonstrate that pharmacological inhibition of CYP2E1 by 1-(4-methyl-5-thiazolyl) ethenone (Q11) exhibits significant therapeutic efficacy in 3 RA animal models. Mechanistically, CYP2E1 inhibition attenuates inflammation by suppressing macrophage M1 polarization and exerts immunosuppressive effects via regulating the Th17/Treg balance. Our study identifies elevated anti-CYP2E1 autoantibodies in RA patients, advancing understanding of RA pathogenesis and providing a novel potential biomarker. Furthermore, we demonstrate that CYP2E1 inhibition ameliorates RA by regulating inflammation and immunity, providing a promising dual-targeting therapeutic strategy for RA. SIGNIFICANCE STATEMENT: This study identifies elevated anti-CYP2E1 autoantibodies in rheumatoid arthritis, revealing a previously unrecognized autoimmune target and potential biomarker. It further demonstrates that CYP2E1 inhibition alleviates disease by concurrently modulating inflammatory responses and immune balance, highlighting a promising dual-target therapeutic strategy.