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Abstract Background Bone morphogenetic proteins (BMP) are evolutionarily conserved morphogens that are reactivated in lung carcinomas. In lung cancer cells, BMP signaling suppresses AMP activated kinase (AMPK) by inhibiting LKB1. AMPK is activated by mitochondrial stress that inhibits ATP production, which is enhanced 100-fold when phosphorylated by LKB1. Activated AMPK can promote survival of cancer cells but its “hyperactivation” induces cell death. The studies here reveal novel cell death mechanisms induced by BMP inhibitors, together with agents targeting the mitochondria, which involves the “hyperactivation” of AMPK. Methods This study examines the synergistic effects of two BMP inhibitors together with mitochondrial targeting agents phenformin and Ym155, on cell death of lung cancer cells expressing LKB1 (H1299), LKB1 null (A549), and A549 cells transfected with LKB1 (A549-LKB1). Cell death mechanisms evaluated were the activation of caspases and the nuclear localization of apoptosis inducing factor (AIF). A769662 was used to allosterically activate AMPK. Knockdown of BMPR2 and LKB1 using siRNA was used to examine their effects on nuclear localization of AMPK. Validation studies were performed on five passage zero primary NSCLC. Results Both BMP inhibitors synergistically suppressed growth when combined with Ym155 or phenformin in cells expressing LKB1. The combination of BMP inhibitors with mitochondrial targeting agents enhanced the activation of AMPK in lung cancer cells expressing LKB1. Allosteric activation of AMPK with A769662 induced cell death in both H1299 and A549 cells. Cell death induced by the combination of BMP inhibitors and mitochondrial-targeting agents did not activate caspases. The combination of drugs induced nuclear localization of AIF in cells expressing LKB1, which was attenuated by knockdown of LKB1. Knockdown of BMPR2 together with Ym155 increased nuclear localization of AIF. Combination therapy also enhanced cell death and AIF nuclear localization in primary NSCLC. Conclusions These studies demonstrate that inhibition of BMP signaling together with mitochondrial targeting agents induce AIF caspase-independent cell death, which involves the “hyperactivation” of AMPK. AIF caspase-independent cell death is an evolutionarily conserved cell death pathway that is infrequently studied in cancer. These studies provide novel insight into mechanisms inducing AIF caspase-independent cell death in cancer cells using BMP inhibitors. Video Abstract