Update publication information. Palytoxin (PLTX) is a polyether Marine toxin isolated from sea anemones. It is one of the most toxic non-protein substances, causing many people to be poisoned every year and die in severe cases. With its known impact on Na+, K+-ATPase, much still remain unclear about the mechanism of PLTX action. Here, we tested different concentrations of PLTX on HaCaT cells, and studied its distributions in cells, its impact on gene expressions, and associated pathways using proteomics combined with bioinformatics tools. We found that PLTX could cause ferroptosis in HaCaT cells, a new type of programmed cell death, by up-regulating the expressions of VDAC3, ACSL4, and NCOA4 that lead to the occurrence of ferroptosis. PLTX also acts on MAPK pathway that is related to cell apoptosis, proliferation, division and differentiation. Different from that of ferroptosis, PLTX down-regulates the expression of ERK, and as a result, the expressions of MAPK1, MAP2K1 and MAP2K2 are also lower which will affect cell proliferation. The genes from these two mechanisms showed interactions but we didn’t find overlap genes between the two. Both ferroptosis and MAPK pathways can be used as anticancer targets, so PLTX may become an anticancer drug with appropriate modification.