Long non-coding RNAs in cancer glycolysis and metabolism: mechanisms and translational opportunities

Abstract Long non-coding RNAs (lncRNAs) have emerged as critical regulators of cancer metabolism, particularly in the reprogramming of glycolysis that supports tumor growth and survival. Once considered non-functional genomic “noise”, lncRNAs influence metabolic adaptation by modulating glycolytic enzymes, transcription factors, and signaling pathways, while also shaping the tumor microenvironment through immune and stromal interactions. In addition, lncRNA-encoded micropeptides provide an extra layer of metabolic control, underscoring their functional diversity. These features indicate lncRNAs as promising diagnostic biomarkers and therapeutic targets, particularly in the context of personalized cancer treatments. RNA-based therapies demonstrate preclinical efficacy in targeting glycolytic lncRNA and reversing drug resistances. Nonetheless, challenges remain, including delivery specificity, off-target effects, and limited clinical validation. Advances in single-cell multi-omics, spatial transcriptomics, and artificial intelligence may offer new avenues to overcome these challenges. Collectively, lncRNAs represent both mechanistic drivers of glycolysis and promising targets for innovative diagnostic and therapeutic strategies in cancer.