Decoding the hepatic fibrosis-hepatocellular carcinoma axis: from mechanisms to therapeutic opportunities

Abstract

Background: Hepatocellular carcinoma (HCC) ranks as the sixth most prevalent malignant neoplasm globally and represents the third-leading cause of cancer-associated mortality worldwide. Epidemiological data indicate that 80-90% of HCC cases demonstrate documented progression from hepatic fibrosis or cirrhosis. This fibrotic-carcinogenic continuum represents a complex multistep pathological cascade, with mechanistic insights being progressively revealed through contemporary investigations.

Objective: This review systematically elucidates the mechanistic contributions of dysregulated signaling pathways and immune microenvironmental remodeling during hepatic fibrocarcinogenesis.

Methods: A systematic online screening protocol was implemented across multiple biomedical databases to curate relevant studies elucidating mechanisms underlying fibrosis-driven hepatocarcinogenesis.

Results: This work conducts a comprehensive pathophysiological analysis of hepatic fibrosis-HCC transition, including dysregulated cytokine networks, dynamic extracellular matrix (ECM) remodeling, epigenetic dysregulation, immune landscape reprogramming, persistent oxidative stress, and acquired mitochondrial dysfunction. The analysis comprehensively evaluates widely utilized experimental models in fibrotic liver carcinogenesis research, while critically assessing emerging biomarkers and mechanism-based therapeutic targets.

Conclusion: This synthesis lays conceptual foundations for advancing translational research on biomarker discovery and precision therapeutics, while offering substantive guidance for developing mechanistically informed strategies to optimize clinical outcomes in hepatic fibrosis and HCC management.

Keywords: Hepatic stellate cells; Hepatocellular carcinoma; Liver fibrosis; Signaling pathways; Tumor microenvironment.