The ERK-cPLA2-ACSL4 axis mediating M2 macrophages ferroptosis impedes mucosal healing in ulcerative colitis

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.