Pseudolaric acid B promotes lung cancer cells ferroptosis depending on JNK/ERK-mediated upregulation of survivin

Lung cancer is one of the most common malignant tumors worldwide, seriously threatening human health. PAB (pseudolaric acid B), an extract of pseudolarix amabilis, has exhibited notable anticancer properties. Nevertheless, the molecular mechanisms underlying PAB-induced anticancer activities remain controversial in lung cancer especially. Herein we aim to investigate the role of IAPs in PAB-induced anticancer effects. PAB selectively inhibits the viability of lung cancer cells and downregulates the expression of IAPs. Transcriptomic analysis suggests that PAB induces lung cancer cells ferroptosis. PAB indeed promotes ferroptotic cell death since PAB enhances lipid oxidation and Fe2+ content. Interestingly, PAB markedly enhances Survivin expression. Suppression of Survivin abolishes PAB-induced ferroptosis. PAB significantly strengthens JNK and ERK kinase activities. We further demonstrate suppression of JNK/ERK reversed PAB-mediated-cytotoxicity, meanwhile restores the expression of Survivin and ferroptosis-related proteins. Consistently, xenograft tumor model results also support that PAB induces ferroptosis through Survivin upregulation. Collectively, we demonstrate PAB induces ferroptosis in lung cancer cells in vivo and in vitro depending on JNK and ERK-mediated Survivin upregulation, providing novel insight for clinical administration of PAB in lung cancer.