Modulation of Inflammation-Driven Hepatocarcinogenesis: The Hepatic Immune Microenvironment, Gut–Liver Axis, and Neuroregulation

Abstract

Abstract Hepatocellular carcinoma (HCC) is a highly malignant cancer closely related to the chronic inflammation induced by persistent liver damage. Various risk factors, including chronic hepatitis B/C virus infections, alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease, aflatoxins exposure, and metabolic disorders, contribute to genetic mutations in hepatocytes, leading to sustained cellular damage and apoptosis. These processes foster a chronic inflammatory microenvironment that activates hepatic stellate cells, promotes extracellular matrix deposition, and triggers aberrant regenerative repair, ultimately advancing liver fibrosis, cirrhosis, and HCC. The transition from chronic liver injury to HCC is governed by two interconnected mechanistic layers: initiating triggers—viral infection and hepatocyte death—that provide the substrate for malignant transformation, and modulatory systems that determine the trajectory of this process. Recent studies have revealed that diverse cell types and molecular signaling pathways form an intercellular regulatory network that fosters an inflammatory and carcinogenic microenvironment. This review focuses on three such modulatory systems—the hepatic immune microenvironment, the gut–liver axis, and neuroregulation—and examines how their interplay influences malignant behaviors including cell transformation, proliferation, and apoptosis. We systematically overview the key cellular constituents, fundamental molecular mechanisms, and core signaling pathways governing inflammation-induced hepatocarcinogenesis, and discuss potential therapeutic targets emerging from current research. A deeper understanding of these fundamental pathological mechanisms provides a conceptual framework for elucidating the initiation and progression of HCC. It also offers a theoretical basis for the future development of preventive and targeted therapeutic strategies, although the translation of these mechanistic insights into clinically effective interventions—particularly for cancer prevention—will require rigorous validation in large-scale, prospective human studies.