Inflammation-associated hepatocellular carcinoma: a revised comprehensive review from pathogenesis to precision prevention and treatment

Xiaoyun Chen¹, Shan Ji^2*

¹Infirmary of Beijing Institute of Graphic Communication, Beijing 100069, China.

²Department of Infectious Diseases, Beijing You’an Hospital, Capital Medical University, Beijing 100069, China.

*Correspondence:

Shan Ji; Email: jsshjdd@163.com

Abstract

Hepatocellular carcinoma (HCC) develops predominantly on the background of chronic liver inflammation. This revised review focuses on how different etiologies-metabolic dysfunction-associated steatotic liver disease (MASLD, formerly non-alcoholic fatty liver disease), viral hepatitis, alcohol-related liver disease, and cholestatic or autoimmune liver disorders-converge on common inflammatory programs while retaining distinct immunometabolic and carcinogenic features. We summarize mechanistic evidence linking persistent hepatocyte injury to activation of NF-κB, IL-6/JAK/STAT3, TLR4/MyD88, COX-2/PGE2, oxidative stress, endoplasmic reticulum stress, ferroptosis, and stromal remodeling, and further discuss how these pathways reprogram macrophages, T lymphocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and hepatic progenitor cells within the tumor microenvironment. Emphasis is placed on the translational bridge from mechanism to clinic, including inflammation-related serum markers, radiomics-clinical nomograms, model development methods, validation metrics, and pathways for clinical implementation. We also critically discuss unresolved issues, including the dual role of regulatory T cells in MASLD/metabolic dysfunction-associated steatohepatitis (MASH), etiology-specific differences in immunotherapy biomarkers, and the challenge of distinguishing causality from association in gut microbiome-HCC studies. Finally, we outline therapeutic strategies that target inflammatory signaling and the immune microenvironment, from immune checkpoint inhibitors and rational local-systemic combinations to pathway-directed small molecules, cell therapy, and nucleic acid delivery platforms. Together, these advances support a precision framework for risk stratification, early detection, and individualized intervention in inflammation-associated HCC.

Keywords:hepatocellular carcinoma, chronic liver inflammation, tumor microenvironment, immunotherapy