Yao Ting, Dong Xiangmin, Lv Jiawen, Fu Liyun, Li Lanjuan
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China.
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City 310003, China; Department of Hepatology, Ningbo No.2 Hospital, China.
Int Immunopharmacol. 2025 Sep 23;162:115151. doi: 10.1016/j.intimp.2025.115151. Epub 2025 Jul 3.
Ulcerative colitis (UC) is a relapsing inflammatory bowel disease with limited effective treatment options. Ferroptosis, characterized by lipid peroxidation-induced cellular death, is involved in UC pathogenesis. Propionic acid, a short-chain fatty acid, has demonstrated therapeutic potential in alleviating numerous conditions; however, its role and underlying mechanisms in UC remain unclear. In this study, we analyzed ferroptosis in UC patients using datasets from the GEO database and established an experimental colitis model to evaluate the therapeutic effects of propionate. We assessed the markers of inflammation and ferroptosis. Our findings revealed that ferroptosis occurred in the colonic tissue of UC patients and mouse colitis model. Propionate effectively alleviated UC symptoms, reduced pro-inflammatory cytokines, and regulated iron homeostasis. At a dose of 100 mM, propionate promoted intestinal epithelial regeneration, while 400 mM inhibited ferroptosis significantly. Mechanistic studies demonstrated that propionate increased the expression of transferrin receptor 1 (TFR1) and ferritin heavy chain 1 (FTH1) in a dose-dependent manner, which was associated with reduced hypoxia-inducible factor 1α (HIF-1α) expression. Moreover, after inhibition of HIF-1α, the therapeutic effects of propionate on colonic symptoms were found to be similar. Furthermore, propionate promoted the polarization of macrophages to the M2 type. Our results indicate that propionate regulates HIF-mediated expression of TFR1 and FTH1 to modulate iron homeostasis, promote epithelial regeneration, inhibit ferroptosis, and regulate macrophage differentiation. These results strongly support the potential use of propionate in the clinical treatment of UC.
溃疡性结肠炎（UC）是一种复发性炎症性肠病，有效治疗选择有限。铁死亡以脂质过氧化诱导的细胞死亡为特征，参与UC的发病机制。丙酸是一种短链脂肪酸，已显示出在缓解多种病症方面的治疗潜力；然而，其在UC中的作用和潜在机制仍不清楚。在本研究中，我们使用来自GEO数据库的数据集分析了UC患者的铁死亡情况，并建立了实验性结肠炎模型以评估丙酸盐的治疗效果。我们评估了炎症和铁死亡的标志物。我们的研究结果显示，铁死亡发生在UC患者的结肠组织和小鼠结肠炎模型中。丙酸盐有效缓解了UC症状，减少了促炎细胞因子，并调节了铁稳态。在100 mM的剂量下，丙酸盐促进了肠上皮再生，而400 mM则显著抑制了铁死亡。机制研究表明，丙酸盐以剂量依赖的方式增加了转铁蛋白受体1（TFR1）和铁蛋白重链1（FTH1）的表达，这与缺氧诱导因子1α（HIF-1α）表达的降低有关。此外，抑制HIF-1α后，发现丙酸盐对结肠症状的治疗效果相似。此外，丙酸盐促进巨噬细胞向M2型极化。我们的结果表明，丙酸盐调节HIF介导的TFR1和FTH1表达以调节铁稳态，促进上皮再生，抑制铁死亡，并调节巨噬细胞分化。这些结果有力地支持了丙酸盐在UC临床治疗中的潜在应用。
