The LINC02041/SRSF1 Axis Facilitates Aerobic Glycolysis and Stemness Maintenance in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) remains one of the most aggressive and lethal malignancies worldwide, with high rates of metastasis and recurrence contributing to its poor prognosis. There is an urgent need to elucidate the molecular mechanisms driving HCC progression and to develop effective therapeutic strategies. Metabolic reprogramming, especially aerobic glycolysis known as the Warburg effect, is a well-established hallmark of cancer. Concurrently, cancer stem cells (CSCs) play crucial roles in tumor initiation, therapy resistance, and recurrence. However, the involvement of long non-coding RNAs (lncRNAs) in linking metabolic alterations and stemness remains poorly understood. In this investigation, we identified LINC02041 as a significantly upregulated lncRNA in HCC tissues and demonstrated its oncogenic role in promoting cell proliferation. We found that STAT3 transcriptionally activates LINC02041 expression. Mechanistically, LINC02041 enhances the stability of SRSF1 protein by suppressing its ubiquitin-mediated degradation, thereby facilitating HCC cell proliferation, migration, glycolytic metabolism, and acquisition of stem-like properties. Our findings delineate a novel STAT3/LINC02041/SRSF1 regulatory axis that coordinately modulates glycolytic reprogramming and stemness maintenance in hepatocarcinogenesis. This study not only advances our understanding of HCC pathophysiology but also identifies LINC02041 as a promising prognostic biomarker and a compelling therapeutic target for novel therapeutic strategies against this aggressive malignancy.