Long non-coding RNAs and autophagy: dual drivers of Hepatocellular carcinoma progression

Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide, is characterized by poor prognosis, high recurrence rates, and limited responsiveness to current therapies. Autophagy, a conserved catabolic pathway essential for cellular homeostasis, plays a paradoxical role in HCC, acting as a tumor suppressor during initiation but promoting survival and progression in advanced stages. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of autophagy, influencing tumorigenesis, metastasis, and therapy resistance through mechanisms such as miRNA sponging, chromatin remodeling, and protein interactions. This review describes how autophagy contributes to HCC at different stages, outlines the dual functions of lncRNAs as oncogenic drivers or tumor suppressors, and illustrates their integration into key signaling networks of autophagy (e.g., PI3K/AKT/mTOR, AMPK, Beclin-1). LncRNAs have been shown to modulate drug resistance, including resistance to first-line agents, by altering autophagic flux and associated molecular pathways. We also explored emerging strategies for targeting the lncRNA-autophagy axis, such as siRNAs, antisense oligonucleotides, and CRISPR/Cas systems, that have shown promise in preclinical studies and may be adapted for HCC. Furthermore, autophagy-related lncRNAs hold potential as non-invasive diagnostic and prognostic biomarkers and as predictors of recurrence. Integrating multi-omics approaches to validate these candidates will be critical for translation into clinical practice. Collectively, this review highlights the lncRNA-autophagy network as a promising frontier of biomarker discovery for precision diagnostics and targets for innovative therapeutics. The regulatory role of lncRNAs in autophagy presents a paradigm shift, heralding new strategies for targeted treatment.