We reported that TLR4‐AKT signaling pathway was activated by lipopolysaccharides (LPS) in HCC cell lines to enhance the cancer stemness capacity, which was reflected by the increased percentage of CD133+CD49f+ population and side population, enhanced sphere formation, and the upregulation of stemness marker gene‐SOX2. The gene discussed is SOX2; the disease is hepatocellular carcinoma.