Hepatocellular Carcinoma Etiology and Molecular Signaling

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a major cause of cancer-related mortality worldwide. It develops mainly in response to chronic liver injury caused by hepatitis B and C virus infections, alcohol abuse, metabolic dysfunction-associated steatotic liver disease (MASLD), aflatoxin exposure, and hereditary metabolic disorders. Persistent inflammation promotes oxidative stress, hepatocyte injury, and activation of hepatic stellate cells, leading to fibrosis and cirrhosis, the principal risk factor for HCC. The cirrhotic liver creates a tumor-promoting microenvironment characterized by continuous tissue injury, regeneration, hypoxia, and genomic instability. HCC progression is further driven by dysregulation of key signaling pathways, including Wnt/ß-catenin, PI3K/Akt/mTOR, MAPK, JAK/STAT, and TGF-ß, which regulate cell proliferation, survival, angiogenesis, invasion, and metastasis. Understanding the interactions among chronic inflammation, fibrosis, cirrhosis, and molecular signaling is essential for identifying biomarkers and developing effective strategies for HCC prevention, early diagnosis, and targeted therapy.