通过靶向BCL2家族蛋白诱导癌细胞死亡已经在治疗癌症方面获得了成功。例如，ABT-737等BH3类模拟剂不仅诱导细胞死亡，还能激活自噬作用。BH3类模拟剂诱导自噬的分子机制仍有争议。在这项研究中，我们展示了BCL2/BCLXL/BCLw抑制剂纳维多柏和MCL1抑制剂S63845在小鼠胚胎成纤维细胞(MEFs)和白血病细胞系中都能够诱导细胞凋亡和自噬，而纳维多柏和S63845在白血病细胞系中诱导的自噬需要抑制半胱天冬酶活性。进一步实验证明，纳维多柏或S63845诱导的自噬不依赖于Beclin 1，但在Bax/Bak之后。此外，纳维多柏和S63845处理诱导MEFs中mtDNA的释放，激活STING从而诱导自噬，而STING KO抑制了纳维多柏和S63845诱导的自噬。此外，STING KO减弱了导致的癌细胞凋亡，这表明STING激活增强了而不是抑制了细胞凋亡。因此，我们的发现为纳维多柏或S63845诱导自噬和细胞死亡的调节提供了新的见解。©2023年，作者(们)独家许可Springer Nature B.V.

Targeting BCL2 family proteins to induce cancer cell death has been successful in the treatment of cancer. BH3 mimetics such as ABT-737 not only induce cell death, but also activate autophagy. The molecular mechanism by which the BH3 mimetics induce autophagy is still controversial. In this study, we show that the BCL2/BCLXL/BCLw inhibitor navitoclax and the MCL1 inhibitor S63845 induce both apoptosis and autophagy in mouse embryonic fibroblasts (MEFs) and leukemia cell lines, while autophagy induced by navticlax and S63845 in leukemia cell lines requires the inhibition of caspase activities. Further experiments demonstrate that the autophagy induced by navitoclax or S63845 does not depend on Beclin 1, but downstream of Bax/Bak. Moreover, both navitoclax and S63845 treatment induce mtDNA release in MEFs, which activates STING and thereby induces autophagy, while STING KO inhibits both navitoclax- and S63845-induced autophagy. Furthermore, STING KO diminishes navitoclax- or S63845-induced apoptosis, suggesting that STING activation enhances rather than inhibits apoptosis. Thus, our findings provide new insights into the regulations of navitoclax- or S63845-induced autophagy and cell death.© 2023. The Author(s), under exclusive licence to Springer Nature B.V.