Due to over-nutrition and lack of exercise, the number of overweight and obese people in the world had surged in the past three decades, and is becoming one of the most serious public health problems worldwide. Extensive epidemiological studies reveal that obesity has major impacts on both the type and incidence of cancers. However, the exact molecular mechanisms underlying obesity-associated cancer are not fully understood yet. Using mouse models, we have recently found that dietary or genetic obesity provokes alterations of gut microbiota profile, thereby increasing the levels of deoxycholic acid (DCA), a gut microbial metabolite produced solely by the 7α-dehydroxylation of primary bile acids. The enterohepatic circulation of DCA increases the levels of DCA in liver and provokes DNA damage-induced cellular senescence in hepatic stellate cells (HSCs), which in turn, secretes various inflammatory and tumor promoting factors in the liver, thus facilitating hepatocellular carcinoma (HCC) development in obese mice. Notably, signs of cellular senescence and associated secretory phenotypes were also observed in the HSCs in the area of HCC arising in patients with non-alcoholic steatohepatitis (NASH) without cirrhosis, implying that a similar pathway is likely to contribute to at least certain aspects of obesity-associated HCC development in humans as well. In this review, we will provide an overview of our recent work and discuss the next steps, toward potential clinical applications of our findings.