Hepatocellular carcinoma (HCC) progresses asymptomatically over several decades after chronic exposure to multiple hepatotoxins. Here, we aimed to identify molecules revealing the malignant onset and progression of liver diseases. From a transcriptomic analysis of a HCC mouse model, ingenuity pathway analysis (IPA) was used to determine the involved causal signaling networks, and relevant genes were validated to identify early biomarkers. The relevant findings were validated in the blood of high-fat diet, alcohol-associated liver disease (ALD), and metabolic dysfunction-associated steatotic liver disease (MASLD) in vivo models, as well as in ALD patients. Ten IPA-predicted causal signaling networks were associated with HCC progression. The expression of cyclin-dependent kinase inhibitor 1a (Cdkn1a) gene, commonly known as P21, was the most dysregulated, and its total (CDN1A/P21) and phosphorylated protein level was increased from early to late stages. P21 was also increased and released into the bloodstream of ALD and MASLD models, both based on multiple hepatotoxins linked to HCC development, as well as in the bloodstream of ALD patients. In conclusion, P21 is altered from early stages of liver diseases leading to HCC, which betrays the onset of liver cancer before developing malignant traits; thus, P21 offers a critical therapeutic window for timely detection of high-risk patients.