Here, we showed that (i) activated HSCs promoted stem cell-like phenotypes in residual HCC cells following sublethal heat treatment through secreting POSTN; (ii) POSTN regulated the stemness of heat-exposed residual HCC via integrin β1/AKT/GSK-3β/β-catenin/TCF4/Nanog signaling pathway; (iii) metformin, an anti-diabetic drug, inhibited progression of heat-exposed residual HCC through suppressing POSTN secretion. This evidence concerns the gene POSTN and hepatocellular carcinoma.