Gadd45α (growth arrest and DNA damage inducible alpha) is a member of a group of genes whose transcript levels are increased following stressful conditions that lead to growth arrest and treatment with agents that lead to DNA damage. Gadd45α is upregulated in liver cirrhosis (LC), hepatic cancer (HC), acute liver failure (AHF) and non-alcoholic fatty liver disease(NAFLD). Here, we investigated the essential differences in the Gadd45α signaling pathway in these diseases at the transcriptional level. The results showed that 44, 46, 71 and 27 genes significant changes in these diseases, and the H-cluster showed that the expression of the Gadd45α signaling-related genes was significantly different in the four liver diseases. DAVID functional analysis showed that the Gadd45α signaling pathway-related genes were mainly involved in cell adhesion and migration, cell proliferation, apoptosis, stress and inflammatory responses, etc. Ingenuity pathway analysis (IPA) software was used to predict the functions of the Gadd45α signaling-related genes, and the results indicated that there were significant changes in cell differentiation, DNA damage repair, autophagy, apoptosis and necrosis. Gadd45α signaling pathway is involved in four kinds of liver disease and regulates a variety of activities via P38 MAPK, NF-κB, mTOR/STAT3, P21, PCNA, PI3K/Akt and other signaling pathways. Modulation of Gadd45α may be exploited to prevent the progression of liver disease, and to identify specific treatments for different stages of liver disease. In summary, the Gadd45α signaling pathway is involved in four kinds of liver disease and regulates a variety of physiological activities through various signaling pathways.