Adaptive drug resistance mechanisms driven by non-coding RNA–protein interaction networks in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) remains a major cause of cancer mortality due to profound heterogeneity and persistent therapeutic resistance. This review summarizes recent mechanistic advances showing how noncoding RNAs (ncRNAs)—including lncRNAs and circRNAs—cooperate with RNA-binding proteins (RBPs) to regulate ferroptosis, autophagy, lipid metabolism, immune evasion, and transcriptional programs. We highlight emerging principles involving RNA chemical modifications, structural elements, and liquid–liquid phase separation that define the specificity of ncRNA–RBP interactions. Recent multi-omics and spatial profiling technologies are also discussed for their role in revealing resistance-associated ncRNA–protein networks. Importantly, this review integrates these findings to outline actionable therapeutic opportunities and the translational potential of targeting ncRNA–RBP axes, emphasizing their relevance to precision oncology. By defining the key regulatory circuits that drive adaptive resistance, this work provides a conceptual framework that may guide biomarker development and personalized treatment strategies in HCC.