N4-acetylcytidine modification of LINC02802 promotes non-small cell lung cancer progression by modulating mitochondrial NAD+/NADH ratio.

Abstract

Long non-coding RNAs (lncRNAs) have emerged as key regulators of cancer progression through their interaction with microRNAs and modulation of gene expression. However, their role in mitochondrial metabolism, particularly in non-small cell lung cancer (NSCLC), remains poorly defined. In this study, we found that LINC02802 was significantly upregulated in NSCLC tissues and associated with poor prognosis. Mechanistically, LINC02802 acts as a competing endogenous RNA (ceRNA) for miR-1976, thereby relieving the suppression of solute carrier family 25 member 51(SLC25A51). Elevated SLC25A51 enhances mitochondrial NAD⁺ import, leading to an increased NAD⁺/NADH ratio and promoting oxidative TCA cycle flux. Functionally, this shift supports tumor cell proliferation and migration. Rescue experiments confirmed that the oncogenic effect of LINC02802 is dependent on the miR-1976/SLC25A51 axis. Interestingly, either silencing LINC02802 with antisense oligonucleotides (ASOs) or treating cells with fludarabine phosphate, an SLC25A51 inhibitor, successfully reversed cisplatin resistance in lung cancer cells. Our findings reveal a novel lncRNA-microRNA-metabolic axis wherein LINC02802 facilitates NSCLC progression by reprogramming mitochondrial metabolism via miR-1976-mediated upregulation of SLC25A51. Targeting this axis may offer therapeutic potential for metabolic intervention in NSCLC.