MicroRNA Landscape in Hepatocellular Carcinoma: Metabolic Re-Wiring, Predictive and Diagnostic Biomarkers, and Emerging Therapeutic Targets

Abstract

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, in part due to late diagnosis and limited prognostic tools. In recent years, microRNAs, small, non-coding regulators of gene expression, have emerged as key modulators of tumor metabolism, microenvironmental crosstalk, and therapeutic response in HCC. This narrative review synthesizes evidence published from January 2000 through April 2025, focusing on four interrelated themes: (1) miRNA-driven metabolic rewiring; (2) circulating and exosomal miRNAs as diagnostic and (3) predictive biomarkers; (4) miRNA-based therapeutic strategies. We conducted a targeted PubMed search using terms related to HCC, miRNA biology, biomarkers, metabolism, and therapy, supplemented by manual reference mining. Preclinical and clinical studies reveal that loss of tumor-suppressor miRNAs and gain of oncomiRs orchestrate glycolysis, lipid and glutamine metabolism, and stromal-immune remodeling. Circulating miRNA signatures, including single- and multimarker panels, demonstrate diagnostic AUCs up to 0.99 for early-stage HCC and distinguish HCC from cirrhosis more accurately than alpha-fetoprotein. Predictively, miRNAs such as miR-21 and miR-486-3p correlate with sorafenib resistance, while tissue and exosomal miRNAs forecast recurrence and survival after curative therapy. Therapeutic manipulation, restoring tumor-suppressor miRNAs via mimics or AAV vectors and inhibiting oncomiRs with antagomirs or LNA oligonucleotides, yields potent anti-tumor effects in models, affecting cell cycle, apoptosis, angiogenesis, and immune activation. Despite technical and delivery challenges, early-phase trials validate target engagement and inform safety optimization. In this review, we highlight opportunities to integrate miRNA biomarkers into surveillance algorithms and combine miRNA therapeutics with existing modalities, charting a roadmap toward precision-guided management of HCC.

Keywords: diagnostic biomarkers; hepatocellular carcinoma; metabolic rewiring; miRNA-based therapeutics; microRNA; predictive biomarkers.

Figure 1

The miRNA Blueprint of Hepatocellular Carcinoma. Schematic overview of the multifaceted roles of microRNAs in hepatocellular carcinoma (HCC). The graphic is partitioned into four panels: 1. Metabolic Re-Wiring: Loss of tumor-suppressor miRNAs (e.g., miR-122, miR-199a-5p, miR-3662) and gain of oncomiRs (miR-23a, miR-192-5p) remodel glucose, lipid, and glutamine metabolism to favor the Warburg phenotype and fatty-acid oxidation. 2. Microenvironment Modulation: Tumor-derived exosomal miRNAs (miR-21-5p, miR-452-5p, miR-1247-3p) skew macrophages to an M2/TAM phenotype and activate CAFs; conversely, miR-206/miR-99b repolarize TAMs to M1, while miR-138-5p and miR-101 restrain angiogenesis and vascular mimicry. 3. Diagnostic and Predictive Biomarkers: Circulating and exosomal miRNAs (single markers such as miR-21, miR-122, or multi-miRNA panels) achieve AUCs up to ~0.99 for early HCC detection, differential diagnosis vs. cirrhosis, and prognostication (miR-221, miR-30d) or therapy response (miR-21, miR-486-3p). 4. Emerging Therapeutics: Replacement of tumor-suppressor miRNAs (miR-26a-AAV, miR-34a-liposome, miR-199a-3p mimics) and inhibition of oncomiRs (anti-miR-21 LNA, anti-miR-221 ASO) delivered via viral vectors, lipid nanoparticles, GalNAc-ASO, or ultrasound-microbubble platforms. Only the most notable miRNAs are shown in each category; arrows indicate up- or down-regulation in HCC. AAV = adeno-associated virus; ASO = antisense oligonucleotide; CAF = cancer-associated fibroblast; TAM = tumor-associated macrophage. “*” denotes most notable miRNAs mentioned in all four categories in the figure.