Abstract：
Ulcerative colitis (UC) is a chronic gastrointestinal disease that can be managed with 5-aminosalicylic acid (5-ASA), the standard treatment for UC. However, the effectiveness of 5-ASA is not always optimal. Our study revealed that despite 5-ASA treatment, cells continued to experience excessive ferroptosis, which may hinder mucosal healing in UC and limit the success of this treatment approach in achieving disease remission. We found that combining 5-ASA with the ferroptosis inhibitor Fer-1 led to a significant inhibition of ferroptosis in macrophages present in the colon tissue, along with an increase in the proportion of M2 macrophages, suggesting that targeting ferroptosis in M2 macrophages could be a potential therapeutic strategy for alleviating UC. Our study also demonstrated that M2 macrophages are more susceptible to ferroptosis compared to M1 macrophages, and this susceptibility is associated with the activated arachidonic acid (AA) metabolism pathway mediated by ERK-cPLA2-ACSL4. Additionally, we found that the expression of cPLA2 gene pla2g4a was increased in the colon of UC patients compared to healthy controls. Furthermore, targeted metabolomics analysis revealed that the combination treatment group, as opposed to the 5-ASA treatment group, exhibited the ability to modulate AA metabolism. Overall, our findings emphasize the importance of addressing macrophage ferroptosis in order to enhance macrophage anti-inflammation, improve mucosal healing, and achieve better therapeutic outcomes for patients with UC.
摘要：
溃疡性结肠炎（UC）是一种慢性胃肠道疾病，可以用5-氨基水杨酸（5-ASA）治疗，UC的标准治疗。然而,5-ASA的有效性并不总是最佳的.我们的研究表明，尽管5-ASA治疗，细胞继续经历过度的铁死亡，这可能会阻碍UC的粘膜愈合，并限制这种治疗方法在实现疾病缓解方面的成功。我们发现，将5-ASA与铁凋亡抑制剂Fer-1组合可显著抑制结肠组织中存在的巨噬细胞的铁凋亡，随着M2巨噬细胞比例的增加，提示靶向M2巨噬细胞的铁凋亡可能是缓解UC的潜在治疗策略.我们的研究还表明，与M1巨噬细胞相比，M2巨噬细胞更容易发生铁死亡，这种易感性与ERK-cPLA2-ACSL4介导的活化花生四烯酸（AA）代谢途径有关。此外,我们发现,与健康对照组相比,UC患者结肠中cPLA2基因pla2g4a的表达增加.此外，靶向代谢组学分析显示，联合治疗组，与5-ASA治疗组相反，表现出调节AA代谢的能力。总的来说,我们的研究结果强调了解决巨噬细胞铁凋亡以增强巨噬细胞抗炎的重要性，改善粘膜愈合，并为UC患者取得更好的治疗效果。
