Work

C1QTNF1-AS1/miR-346 axis suppresses osteosarcoma progression via dual inhibition of LDHA/PDK1-mediated Warburg effect

Year: 2025

Type: article

Abstract: PURPOSE: Osteosarcoma (OS) relies on the Warburg effect for aggressive growth and chemotherapy resistance, but strategies to disrupt this metabolic adaptation remain limited. This study aimed to identify novel noncoding RNA regulatory mechanisms governing the Warburg effect in OS and explore potential therapeutic targets. MATERIALS AND METHODS: Integrated bioinformatics analysis (GEO dataset GSE126209) was combined with experimental validation (qPCR, Western blotting, dual-luciferase assays) to characterize interactions between long noncoding RNA (LncRNA) C1QTNF1-AS1, microRNA-346 (miR-346), and key glycolytic enzymes. Functional assays (cell proliferation, migration, invasion and glucose/lactate/ATP measurements) were performed to assess metabolic and oncogenic effects in OS cell lines. RESULTS: We identified a previously uncharacterized C1QTNF1-AS1/miR-346/PDK1-LDHA regulatory axis. miR-346 uniquely suppressed both pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA)-rate-limiting nodes in lactic acid production-whereas C1QTNF1-AS1 synergistically enhanced their activities. This dual-targeting mechanism induced a co-metabolic crisis in OS cells, reducing lactate output and reversing chemotherapy resistance in vivo. CONCLUSION: The C1QTNF1-AS1/miR-346 axis reveals a treatable vulnerability in OS metabolism. miR-346 is proposed as a first-class multitarget RNA therapy to weaken the Warburg effect, offering a novel strategy for metabolic intervention in OS.

Source: BMC Cancer

DOI: 10.1186/s12885-025-14935-x