CircPOLA2 sensitizes NSCLC cells to ferroptosis and suppresses tumorigenesis via the Merlin-YAP signaling pathway.

Circular RNAs (circRNAs) have been implicated in the tumorigenesis of non-small cell lung cancer (NSCLC). Ferroptosis is considered a mechanism to suppress tumorigenesis. Herein, we identified a downregulated circRNA, circPOLA2 (hsa_circ_0004291), in NSCLC tissues and found that it was correlated with advanced clinical stage in patients. Nuclear-cytoplasmic fractionation assays and FISH assays confirmed that circPOLA2 was predominantly localized in the cytoplasm. Overexpression of circPOLA2 promoted lipid peroxidation and ferroptosis in NSCLC cells, thereby inhibiting cell proliferation and migration, while knockdown of circPOLA2 exerted the opposite effects. Mechanistically, circPOLA2 interacted with Merlin, a critical regulator of the Hippo pathway, and restricted Merlin phosphorylation at S518, leading to the activation of the Hippo pathway. In addition, circPOLA2 enhanced ferroptosis in NSCLC cells by activating the Hippo pathway. Together, circPOLA2 sensitizes cells to ferroptosis and suppresses tumorigenesis in NSCLC by facilitating Merlin-mediated activation of the Hippo signaling pathway.