IMPAD1 functions as mitochondrial electron transport inhibitor that prevents ROS production and promotes lung cancer metastasis through the AMPK-Notch1-HEY1 pathway.

The tumor microenvironment (TME) and metabolic reprogramming have been implicated in cancer development and progression. However, the link between TME, metabolism, and cancer progression in lung cancer is unclear. In the present study, we identified from the conditioned medium of highly invasive CL1-5. High expression of IMduanyu15631 was associated with a poorer clinical phenotype in lung cancer patients, with reduced survival and increased lymph node metastasis. Knockdown of IMduanyu15631 significantly inhibited migration/invasion abilities and metastasis in vitro and in vivo. Upregulation of IMduanyu15631 and subsequent accumulation of AMP in cells increased the pAMPK, leading to Notch1 and HEY1 upregulation. As AMP is an ADORA1 agonist, treatment with ADORA1 inhibitor reduced the expression of pAMPK and HEY1 expression in cells. IMduanyu15631 caused mitochondria dysfunction by inhibiting mitochondrial Complex I activity, which reduced mitochondrial levels and activated the AMPK-HEY1 pathway. Collectively this study supports the multipotent role of IMduanyu15631 in promotion of lung cancer metastasis by simultaneously increasing AMP levels, inhibition of Complex I activity to decrease duanyu1670 levels, thereby activating AMPK-Notch1-HEY1 signaling, and providing an alternative metabolic pathway in energy stress conditions.

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