Purpose: Many natural compounds derived from plants or microbes show promising potential for anticancer effect.In this study,we discussed the molecular mechanism of neoalbaconol (NA),a novel small-molecular compound isolated from fungus,in cancer cells.Methods: To evaluate the tumor suppression activity of NA,we first observed its effects on the growth of tumor and normal cell lines.To confirm the induction of cell death form,we chose to observe the effects of inhibitors and energy metabolism in NA-treated cells.The molecular mechanisms of NA were determined by western blot,q-PCR and kinase assay.Using the nude mice nasopharyngeal carcinoma (NPC) model,we detected the inhibition effect of NA in vivo.Results: NA selectively inhibited growth in a wide variety of tumor cell lines without significant affect on the normal cell lines.In the cell lines tested,NA induced cell death in a dose-and time-dependent manner;the necroptosis inhibitor necrostatin-1 greatly increased the cell viability.By targeting PDK1,NA reduced the consumption of glucose and ATP generation,and caused apoptotic and necroptotic death of cancer cells through independent pathway.Necroptosis was remarkably induced,which was confirmed by several necroptosis-specific markers: presence of necrotic morphology,increase of receptor-interacting protein kinase 1/3 (RIPK1/RJPK3) colocalization and interaction.The possibility that Akt overexpression reversed the NA-induced energy crisis confirmed the importance of the PDK1-Akt-energy pathway in NA-mediated cell death.Moreover,NA showed the capability to inhibit PI3-K/Akt signaling and suppress tumor growth in the NPC nude mouse model.These results supported the feasibility of NA in anticancer treatments.Conclusion: These findings suggested that NA induces energy depletion of cells assoiated with apoptosis and necroptosis by inhibition of PI3K/Akt signaling pathway in vitro and in vivo;NA induced cell death is mainly caused by necroptosis,a most recently defined non-apoptotic programmed cell death mechanism.Neoalbconol then may have potentials in chemotherapy and chemoprevention as a lead-compound.