Extracellular vesicle–derived LINC02313 stabilizes HNRNPC to drive PKM2-dependent glycolytic reprogramming and proliferation in hepatocellular carcinoma

Increasing evidence highlights the critical roles of long non-coding RNAs (lncRNAs) in tumor initiation and progression, particularly in hepatocellular carcinoma (HCC). Extracellular vesicles (EVs) mediate intercellular communication by transferring functional cargos, including lncRNAs. However, the biological significance of tumor-derived EV-enriched lncRNAs in HCC remains poorly understood. EV-associated lncRNAs were identified through integrative analyses of the TCGA-LIHC and exoRBase datasets. LINC02313 expression was validated in HCC tissues and serum-derived EVs. EVs were isolated and characterized by TEM, nanoparticle tracking analysis, and EV marker profiling. Gain- and loss-of-function assays, together with CCK-8, colony formation, xenograft, and metabolic analyses, were performed to assess the effects of LINC02313 on HCC proliferation and glycolysis. RNA-seq was used to explore downstream pathways. The interaction between LINC02313 and HNRNPC was examined by RNA pulldown, RIP-qPCR, protein stability, ubiquitination, and domain-mapping assays. PKM alternative splicing was assessed by qPCR, Western blotting, and modulation of m 6 A signaling. Here, we identified LINC02313 as an HCC-derived, EV-associated lncRNA through integrative analysis of public datasets and found that it was markedly upregulated in both HCC tissues and serum-derived EVs from patients with HCC. Further analyses showed that EV-delivered LINC02313 could be efficiently transferred into recipient HCC cells, where it promoted malignant progression. Both in vitro and in vivo experiments demonstrated that LINC02313 enhanced HCC cell proliferation and glycolytic activity. Mechanistically, LINC02313 bound to the RNA recognition motif (RRM) domain of HNRNPC through its S2 region, thereby stabilizing HNRNPC protein by preventing its ubiquitin–proteasome-mediated degradation. Further investigation identified BTRC as an E3 ubiquitin ligase involved in HNRNPC ubiquitination and degradation, while LINC02313 disrupted the interaction between BTRC and HNRNPC rather than directly binding to BTRC. Stabilized HNRNPC, in turn, promoted METTL3-mediated modulation of PKM alternative splicing, leading to PKM2 upregulation, enhanced aerobic glycolysis, and increased HCC cell proliferation and tumor progression. EV-derived LINC02313 promotes glycolytic reprogramming and accelerates HCC progression by stabilizing HNRNPC, thereby facilitating PKM2 upregulation. These findings elucidate a previously unrecognized oncogenic mechanism of EV-mediated lncRNA signaling in HCC and identify LINC02313 as a candidate non-invasive biomarker for HCC detection.