BACKGROUND: Ulcerative Colitis (UC) is a condition that causes ulceration and inflammation of the intestinal epithelium. UC treatment depends on macrophages' phenotypic switch from pro-inflammatory (M1) to anti-inflammatory and tissue-repairing (M2). It has been reported that the epigenetic alteration of histone lactylation affects macrophage activity and phenotype. TAK-242, a TLR4 inhibitor, stimulates histone lactylation to generate reparative M2 UC macrophages. METHODS: This review highlighted the significance in terms of introduction, an overview of histone lactylation, the mechanism of action of TAK-242 in regulating inflammatory responses, the relationship between TAK-242 to histone lactylation, the potential role of TAK-242-dependent histone lactylation in macrophage polarization, the role of repair macrophages in ulcerative colitis and regulation of repair macrophages by histone lactylation. RESULTS: Novel treatments for ulcerative colitis involve the use of TAK-242 to enhance histone lactylation, which in turn boosts macrophage function and promotes mucosal healing. CONCLUSION: TAK-242 exhibits therapeutic potential in the treatment of UC, and this research suggests further investigation and clinical trials to enhance patient outcomes.