Collectively, our findings confirm that upregulation of let-7a-5p leads to lung cancer cell death, the underlying mechanism is associated with the autophagy burst induced by the inhibition of BCL2L1 through PI3Kγ signaling pathway, which provide emerging insight into the investigation of lung cancer carcinogenesis and development, and let-7a-5p, as an efficient BCL2L1 inhibitor, might be a useful target for lung cancer treatment. This evidence concerns the gene BCL2L1 and lung cancer.