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Abstract：
Artesunate (ART), a natural product isolated from traditional Chinese plant Artemisia annua, has not been extensively explored for its anti-melanoma properties. In our study, we found that ART inhibited melanoma cell proliferation and induced melanoma cell ferroptosis. Mechanistic study revealed that ART directly targets Ido1, thereby suppressing Hic1-mediated transcription suppression of Hmox1, resulting in melanoma cell ferroptosis. In CD8+ T cells, ART does not cause cell ferroptosis due to the low expression of Hmox1. It also targets Ido1, elevating tryptophan levels, which inhibits NFATc1-mediated PD1 transcription, consequently activating CD8+ T cells. Our study uncovered a potent and synergistic anti-melanoma efficacy arising from ART-induced melanoma cell ferroptosis and concurrently enhancing CD8+ T cell-mediated immune response both in vivo and in vitro through directly targeting Ido1. Our study provides a novel mechanistic basis for the utilization of ART as an Ido1 inhibitor and application in clinical melanoma treatment.
摘要：
青蒿琥酯(ART),从中国传统植物黄花蒿中分离出的天然产物，尚未广泛探索其抗黑色素瘤特性。在我们的研究中,我们发现ART抑制黑色素瘤细胞增殖并诱导黑色素瘤细胞铁凋亡。机制研究表明，ART直接靶向Ido1，从而抑制Hic1介导的Hmox1转录抑制，导致黑色素瘤细胞铁性凋亡。在CD8+T细胞中，由于Hmox1的低表达，ART不会引起细胞铁死亡。它还针对Ido1，提高色氨酸水平，抑制NFATc1介导的PD1转录，激活CD8+T细胞。我们的研究发现了由ART诱导的黑色素瘤细胞铁凋亡引起的有效和协同的抗黑色素瘤功效，并同时通过直接靶向Ido1在体内和体外增强CD8T细胞介导的免疫反应。我们的研究为ART作为Ido1抑制剂的利用和在临床黑色素瘤治疗中的应用提供了新的机制基础。
