SLC25A40 promotes NSCLC growth by enhancing NADPH-mediated lipid synthesis and suppressing ROS accumulation-induced ferroptosis

Mitochondria serve as vital organelles that play critical roles in regulating cell metabolism and maintaining redox homeostasis. Their dysfunctions are closely associated with the progression of multiple human malignancies. SLC25A40 has been predicted as a mitochondrial carrier required for glutathione import into mitochondria. However, the role of SLC25A40 in human cancers, especially in non-small cell lung cancer (NSCLC), remains poorly understood. Here, we found that SLC25A40 expression was elevated in NSCLC. This upregulation was associated with poor prognosis. Silencing SLC25A40 suppressed NSCLC growth by inhibiting cell proliferation and inducing ferroptosis, whereas its overexpression promoted NSCLC growth. Mechanistically, SLC25A40 promotes cell proliferation by increasing NADPH-mediated lipid synthesis and suppresses ferroptosis by decreasing mitochondrial ROS accumulation. Furthermore, we demonstrated that the elevation of SLC25A40 expression in NSCLC cells was primarily due to decreased miR-4299. This research highlights the pivotal role of SLC25A40 in NSCLC progression by modulating both cell proliferation and ferroptosis, suggesting it as a promising therapeutic target in the management of NSCLC.