Inhibition of FTO attenuates Crohn’s Disease injury and inflammation by increasing BACH2 m6A modifications via YTHDF1-dependent mechanisms

Abstract The role of N⁶-methyladenosine (m6A) modifications in colonic inflammation is poorly understood. In this study, we describe the role of fat mass and obesity-associated protein (FTO), whose expression is elevated in Crohn’s disease (CD) models as well as in human colitis samples. In a trinitrobenzene sulfonic acid (TNBS)-induced inflammatory bowel diseases mouse model, inflammation was reduced by FTO knockdown. BACH2 was determined to be a direct substrate of FTO by m6A methylated RNA immunoprecipitation and RNA sequencing analyses. BACH2 is a key regulator of CD4⁺T cells differentiation, alleviating inflammatory diseases by controlling the balance between tolerance and immunity, FTO affects the differentiation of CD4⁺T cells (CD25, CD44 and CD69) by reducing the expression of transcription factor BACH2, thus aggravating colon inflammation. Therefore, anti-inflammatory compounds targeting FTO are expected to alleviate damage in Crohn's disease. On basis of this finding, structure-based screening was used to identify anti-inflammatory activity licochalcone B as a potential FTO inhibitor that directly binds to FTO and attenuates colitis through inhibiting of FTO-BACH2- CD4⁺ T axis.