Acrolein attached mouse cell LC-MS/MS

Dysregulated cell death leading to uncontrolled cell proliferation is a major hallmark of cancer. Chemotherapy-induced cell death is critical for the success of cancer treatment but this process is impaired by metabolic byproducts. How these metabolic byproducts interfere with the efficacies of anti-cancer therapy is unclear. Here, we show that the metabolic byproduct acrolein derived from polyamine metabolic pathways, tobacco smoke or fuel combustion, induces ferroptosis independently of the immune sensor ZBP1, inflammasomes and type I IFN signaling. In addition, acrolein suppresses necroptosis in cancer cells by inhibiting the oligomerization of the necroptosis effector MLKL. Loss of SAT1, a key enzyme in polyamine metabolism responsible for intracellular acrolein production, sensitizes cells to necroptosis. In tumor xenograft models, administration of an acrolein-trapping agent in mice, to remove acrolein and relieve necroptosis blockade, enhances the therapeutic efficacy of the chemotherapeutic agent cyclophosphamide. In humans, patients with high cell death activity but low expression of polyamine metabolism-related genes exhibit improved survival. These findings highlight that the removal of toxic metabolic byproducts that block necroptosis improves the success of certain chemotherapies.