肠粘膜炎是抗癌化疗常见的副作用之一。然而，粘膜炎发展所涉及的分子机制仍不完全清楚。在本研究中，我们研究了受体相互作用蛋白激酶3（RIP3/RIPK3）在调节阿霉素诱导的肠粘膜炎中的功能及其潜在机制。在小鼠中诱导肠粘膜炎动物模型用于体内研究。大鼠肠细胞系IEC-6用于体外研究。 RNA-seq 用于探索阿霉素诱导的肠粘膜炎的转录组变化。使用质谱法对完整糖肽进行表征，以鉴定与粘膜炎相关的 α-1,2-岩藻糖基化蛋白。阿霉素治疗增加肠道中 RIP3 的表达，并引起小鼠严重的肠粘膜炎，消除 RIP3 可消除阿霉素诱导的肠粘膜炎。 RIP3 介导的阿霉素诱导的粘膜炎并不依赖于混合谱系激酶结构域 (MLK​​L)，而是依赖于 α-1,2-岩藻糖基转移酶 2 (FUT2) 催化的炎症相关蛋白上的 α-1,2-岩藻糖基化。 MLKL 缺乏不会影响肠粘膜炎，而 2-脱氧-D-半乳糖 (2dGal) 抑制 α-1,2-岩藻糖基化可显着减轻阿霉素诱导的炎症和粘膜炎。RIP3-FUT2 途径是阿霉素-诱发肠粘膜炎。靶向肠道 RIP3 和/或 FUT2 介导的 α-1,2-岩藻糖基化可能为预防化疗引起的肠道粘膜炎提供潜在靶标。© 2024。作者获得 Springer Nature Switzerland AG 的独家许可。

Intestinal mucositis is one of the common side effects of anti-cancer chemotherapy. However, the molecular mechanisms involved in mucositis development remain incompletely understood. In this study, we investigated the function of receptor-interacting protein kinase 3 (RIP3/RIPK3) in regulating doxorubicin-induced intestinal mucositis and its potential mechanisms.Intestinal mucositis animal models were induced in mice for in vivo studies. Rat intestinal cell line IEC-6 was used for in vitro studies. RNA‑seq was used to explore the transcriptomic changes in doxorubicin-induced intestinal mucositis. Intact glycopeptide characterization using mass spectrometry was applied to identify α-1,2-fucosylated proteins associated with mucositis.Doxorubicin treatment increased RIP3 expression in the intestine and caused severe intestinal mucositis in the mice, depletion of RIP3 abolished doxorubicin-induced intestinal mucositis. RIP3-mediated doxorubicin-induced mucositis did not depend on mixed lineage kinase domain-like (MLKL) but on α-1,2-fucosyltransferase 2 (FUT2)-catalyzed α-1,2-fucosylation on inflammation-related proteins. Deficiency of MLKL did not affect intestinal mucositis, whereas inhibition of α-1,2-fucosylation by 2-deoxy-D-galactose (2dGal) profoundly attenuated doxorubicin-induced inflammation and mucositis.RIP3-FUT2 pathway is a central node in doxorubicin-induced intestinal mucositis. Targeting intestinal RIP3 and/or FUT2-mediated α-1,2-fucosylation may provide potential targets for preventing chemotherapy-induced intestinal mucositis.© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.