Shi Junfeng, Cheng Yifeng, Wang Lixue, Xing Wen, Li Yudi, Sun Xiulin, Lv Yunpeng, Zhang Yichuan, Li Yanming, Zhao Wenhua
School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, China.
School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Free Radic Biol Med. 2025 Jun;233:24-38. doi: 10.1016/j.freeradbiomed.2025.03.031. Epub 2025 Mar 21.
Increase of immature myeloid cells in the bone marrow drives the development of acute myeloid leukemia (AML). The study aimed to clarify the biological function and regulatory mechanism of scavenger receptor class B type 1 (SR-B1) in AML, mainly its effect on ferroptosis and the influences on leukemogenesis and resistance to venetoclax. In this study, we found that the SR-B1 deficiency directly reduced the invasion and promoted death of malignant cells in AML. Strikingly, SR-B1 deficiency could up-regulated the expression of ferroptosis-related proteins to facilitate the occurrence of ferroptosis in vivo, and could also down-regulated the expression of apoptosis related protein B-cell lymphoma-2 (BCL-2). And then, we confirmed SR-B1 inhibitor block lipid transport-1 (BLT-1) had a superior efficacy in AML cells and AML model mice. The study found that whether SR-B1 deficiency or BLT-1 treatment could cause iron deposition and the accumulation of lipid peroxides in vivo, thereby suppressing leukemogenesis through ferroptosis. Critically, we found that SR-B1 inhibitor BLT-1 could reverse drug-resistance of venetoclax to promote AML cells death via ferroptosis. Our finding identified that SR-B1 as a critical regulator of the proliferation in AML which could provide a promising therapeutic strategy against malignant myeloid leukemia cells and drug-resistance.
骨髓中未成熟髓样细胞的增加驱动急性髓系白血病（AML）的发展。本研究旨在阐明B1型清道夫受体（SR-B1）在AML中的生物学功能和调控机制，主要是其对铁死亡的影响以及对白血病发生和对维奈托克耐药性的影响。在本研究中，我们发现SR-B1缺陷直接降低了AML中恶性细胞的侵袭并促进其死亡。令人惊讶的是，SR-B1缺陷可上调铁死亡相关蛋白的表达以促进体内铁死亡的发生，还可下调凋亡相关蛋白B细胞淋巴瘤-2（BCL-2）的表达。然后，我们证实SR-B1抑制剂阻断脂质转运-1（BLT-1）在AML细胞和AML模型小鼠中具有更好的疗效。研究发现，无论是SR-B1缺陷还是BLT-1处理均可导致体内铁沉积和脂质过氧化物积累，从而通过铁死亡抑制白血病发生。至关重要的是，我们发现SR-B1抑制剂BLT-1可逆转维奈托克的耐药性，通过铁死亡促进AML细胞死亡。我们的发现确定SR-B1是AML增殖的关键调节因子，可为对抗恶性髓系白血病细胞和耐药性提供一种有前景的治疗策略。
