Obeticholic acid alleviates lupus pathology by inhibiting T follicular helper cell differentiation

Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by aberrant germinal center (GC) reactions and autoantibody production. Expansion of T follicular helper (T FH ) cells is a hallmark of SLE that contributes to disease progression. Accordingly, T FH cells represent a promising therapeutic target for SLE. Here, we repurposed obeticholic acid (OCA), an FDA-approved drug for primary biliary cholangitis, as a potential treatment for SLE. OCA selectively inhibited the differentiation of T FH cells both in vitro and in vivo by suppressing the transcription factor ETV5, thereby downregulating SPP1 , a key ETV5 target that promotes the development of T FH cells. In lupus-prone mice, OCA treatment reduced T FH - and GC B-cell populations and alleviated lupus-like manifestations, including autoantibody production and tissue pathology. These findings highlight OCA as a promising immunomodulatory candidate for SLE, providing avenues for devising a therapeutic strategy targeting the T FH cell–GC axis in systemic autoimmunity.