Wei Yihong, Liu Wancheng, Wang Ruiqing, Chen Yuhong, Liu Jinting, Guo Xiaodong, Can Can, Yang Xinyu, Wang Dongmei, Hu Xiang, Ma Daoxin
Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
Nanyang Technological University, Nanyang Avenue, Singapore.
Free Radic Biol Med. 2024 Mar;213:36-51. doi: 10.1016/j.freeradbiomed.2024.01.005. Epub 2024 Jan 11.
Short-chain fatty acids (SCFAs), particularly propionate and butyrate, have been reported in many cancers. However, the relationship between propionate and acute myeloid leukemia (AML) remains unclear. Additionally, Acyl-CoA synthetase long chain family member 4 (ACSL4) has been reported to regulate immunity in solid tumors, but there are still many gaps to be filled in AML. Here, we discovered the underlying mechanism of propionate and ACSL4-mediated ferroptosis for immunotherapy. Our results showed that the level of propionate in the AML patients' feces was decreased, which was correlated to gut microbiota dysbiosis. Moreover, we demonstrated that propionate suppressed AML progression both in vivo and in vitro. In mechanism, propionate induced AML cells apoptosis and ferroptosis. The imbalance of reactive oxygen species (ROS) and redox homeostasis induced by propionate caused mitochondrial fission and mitophagy, which enhanced ferroptosis and apoptosis. Furthermore, ACSL4-mediated ferroptosis caused by propionate increased the immunogenicity of AML cells, induced the release of damage-associated molecular patterns (DAMPs), and promoted the maturation of dendritic cells (DCs). The increased level of immunogenicity due to ferroptosis enable propionate-based whole-cell vaccines to activate immunity, thus further facilitating effective killing of AML cells. Collectively, our study uncovers a crucial role for propionate suppresses AML progression by inducing ferroptosis and the potential mechanisms of ACSL4-mediated ferroptosis in the regulation of AML immunity.
短链脂肪酸（SCFAs），尤其是丙酸和丁酸，已在多种癌症中被报道。然而，丙酸与急性髓系白血病（AML）之间的关系仍不清楚。此外，酰基辅酶A合成酶长链家族成员4（ACSL4）已被报道在实体瘤中调节免疫，但在AML中仍有许多空白有待填补。在此，我们发现了丙酸和ACSL4介导的铁死亡用于免疫治疗的潜在机制。我们的结果表明，AML患者粪便中丙酸水平降低，这与肠道微生物群失调相关。此外，我们证明丙酸在体内和体外均抑制AML进展。在机制上，丙酸诱导AML细胞凋亡和铁死亡。丙酸诱导的活性氧（ROS）和氧化还原稳态失衡导致线粒体裂变和线粒体自噬，从而增强铁死亡和凋亡。此外，丙酸引起的ACSL4介导的铁死亡增加了AML细胞的免疫原性，诱导损伤相关分子模式（DAMPs）的释放，并促进树突状细胞（DCs）的成熟。铁死亡导致的免疫原性水平升高使基于丙酸的全细胞疫苗能够激活免疫，从而进一步促进对AML细胞的有效杀伤。总的来说，我们的研究揭示了丙酸通过诱导铁死亡抑制AML进展的关键作用以及ACSL4介导的铁死亡在调节AML免疫中的潜在机制。
