Circ0515 reprogramming mitochondrial succinate metabolism and promotes lung adenocarcinoma progression through regulating SDHB

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide. Its high incidence and poor prognosis are closely associated with complex molecular mechanisms. Circular RNAs (circRNAs), a class of non-coding RNAs, play significant regulatory roles in tumorigenesis and progression. However, their specific functions and mechanisms in lung cancer remain largely unclear. This study aims to elucidate the expression pattern and molecular mechanisms of circ0515 in lung cancer, particularly its roles in tumor proliferation, migration, and metabolism. The study revealed that circ0515 is significantly upregulated in lung cancer tissues and cell lines, specific knockdown of circ0515 using short hairpin RNA (shRNA) or antisense oligonucleotide (ASO) significantly inhibits lung cancer cell proliferation, migration, and xenograft tumor formation. On one hand, circ0515 acts as a molecular sponge for miRNA-328-3p, upregulating its downstream target gene YWHAZ, thereby activating the AKT signaling pathway and significantly promoting lung cancer cell proliferation and migration. On the other hand, circ0515 recruited RNA binding motif protein 45 (RBM45) to stabilize SDHB mRNA, promoting SDHB expression and mitochondrial oxidative phosphorylation and succinate metabolism, leading to increased cisplatin resistance in lung cancer cells. These findings not only advance our understanding of the functional roles of circ0515 in lung cancer but also provide a theoretical basis for considering circ0515 as a potential therapeutic target for NSCLC.