Chronopharmacological effects of 5-aminosalicylic acid in the treatment of experimental colitis in mice

Background5-Aminosalicylic acid (5-ASA) is a first-line therapy for ulcerative colitis, but whether dosing timing influences its therapeutic efficacy remains unclear. This study aims to investigate the chronopharmacological effects of 5-ASA in experimental colitis.MethodsA dextran sulfate sodium (DSS)-induced colitis model was used to compare the therapeutic effects of 5-ASA administered at different Zeitgeber times. Colonic proteomic profiling was performed to identify circadian-responsive proteins associated with differential drug efficacy. Intestinal epithelial-specific Bmal1 knockout mice were used to determine whether the circadian clock regulates the chronopharmacological response to 5-ASA.Results5-ASA showed marked time-dependent efficacy in DSS-induced colitis, with greater protection at ZT14 than at ZT2. Proteomic analysis identified ferritin heavy chain 1 (FTH1) as a circadian-responsive protein associated with differential treatment outcomes. 5-ASA suppressed FTH1 expression, whereas FTH1 overexpression attenuated anti-inflammatory effects of 5-ASA. Moreover, intestinal epithelial-specific deletion of Bmal1 largely abolished diurnal variation in both FTH1 expression and 5-ASA efficacy, indicating that the intestinal clock coordinates the time-dependent response to 5-ASA.ConclusionThese findings identify FTH1 as a circadian-responsive factor linked to the time-dependent efficacy of 5-ASA and support circadian-guided optimization of 5-ASA administration as a potential strategy for improving UC treatment.