An excess fat in the liver enhances the susceptibility to hepatic cancer. We found that Armcx3, a protein only known to date to play a role in neural development, is strongly increased in mouse liver in response to lipid availability and proliferation-inducing insults. In patients, the levels of hepatic Armcx3 are also increased in conditions of high exposure of the liver to fat. We wanted to determine the role of Armcx3 in the hepatocarcinogenesis favored by a high-fat diet. We generated mice with genetically driven suppression of Armcx3, and we found that they were protected against experimentally induced hepatic cancer, especially in conditions of a high-fat diet. Armcx3 was also found to promote hepatic cell proliferation through the interaction with Sox9, a known proliferation factor in hepatocellular carcinoma. Armcx3 is identified as a novel factor in meditating propensity to liver cancer in conditions of high hepatic lipid insults. ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly upregulated in mouse liver in response to high lipid availability, and that hepatic ARMCX3 is upregulated in patients with NAFLD and hepatocellular carcinoma (HCC). Mice were subjected to ARMCX3 invalidation (inducible ARMCX3 knockout) and then exposed to a high-fat diet and diethylnitrosamine-induced hepatocarcinogenesis. The effects of experimental ARMCX3 knockdown or overexpression in HCC cell lines were also analyzed. ARMCX3 invalidation protected mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis. ARMCX3 invalidation promoted apoptotic cell death and macrophage infiltration in livers of diethylnitrosamine-treated mice maintained on a high-fat diet. ARMCX3 downregulation reduced the viability, clonality and migration of HCC cell lines, whereas ARMCX3 overexpression caused the reciprocal effects. SOX9 was found to mediate the effects of ARMCX3 in hepatic cells, with the SOX9 interaction required for the effects of ARMCX3 on hepatic cell proliferation. In conclusion, ARMCX3 is identified as a novel molecular actor in liver physiopathology and carcinogenesis. ARMCX3 downregulation appears to protect against hepatocarcinogenesis, especially under conditions of high dietary lipid-mediated hepatic insult