Extracellular HSP90α inhibits ferroptosis through GPX4 in NSCLC cells

Abstract

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer in the world. Extracellular HSP90α (eHSP90α) promotes epithelial–mesenchymal transition (EMT) and leads to NSCLC resistance in combination with targeted drugs. However, the molecular mechanism by which HSP90α induces EMT is unclear.Here, we used the STRING database to screen for proteins that interact with HSP90α in lung cancer cells, and found that the relationship between HSP90α and GPX4 is essential for ferroptosis in NSCLC cells. We also found that extracellular HSP90α increased E-cadherin expression by silencing LRP1 with siRNA, while decreased N-cadherin, Vimentin, and GPX4 expression, eHSP90α promoted EMT and inhibited ferroptosis by upregulating GPX4. We further found that hrHSP90α and TGF-β1 inhibited ferroptosis.The AKT signaling pathway was involved in eHSP90α-inhibited EMT. Meanwhile, we also confirmed that Ferrostatin-1 and hrHSP90α accelerated gefitinib resistance.These findings suggest that eHSP90α promoted EMT through LRP1 and inhibited ferroptosis by upregulating GPX4 in NSCLC cells. There may be mutual regulation between EMT and ferroptosis, and ferroptosis-inducing therapy may provide a new treatment strategy for gefitinib-resistant NSCLC.