PDIA3 Inhibition Facilitates Sensitivity of IKE‐Induced Ferroptosis via STAT3/LCN2 Axis to Improve Glioblastoma Therapy

Abstract Ferroptosis, an iron‐dependent form of programmed cell death, has emerged as a promising therapeutic approach in glioblastoma (GBM). Nonetheless, the role and mechanism governing vulnerability to ferroptosis in GBM have remained unknown. In this study, we identify protein disulfide isomerase A3 (PDIA3) as a crucial factor mediating the vulnerability of glioma cells to ferroptosis and demonstrate that inhibition or depletion of PDIA3 enhances IKE‐induced ferroptosis in GBM cells. Mechanistically, NEDD4L functions as an E3 ubiquitin ligase to promote ferroptosis by facilitating K29‐linked ubiquitination of PDIA3 via its C‐terminal HECT domain. Furthermore, NEDD4L‐mediated ubiquitination of PDIA3 enhances ferroptosis by downregulating the expression of LCN2 through its interaction with STAT3 independently of ATF4. Here, a drug delivery system is presented using a tetrahedral DNA nanostructure (TDN) encapsulating IKE (TDN‐IKE) to penetrate the blood–brain barrier. The combined use of TDN‐IKE and PDIA3 inhibitors exhibits a synergistic antitumor effect against GBM therapy in vivo, providing a potential therapeutic approach for ferroptosis‐based therapy in GBM. Overall, these findings demonstrate a novel mechanism by which PDIA3 regulates ferroptosis, indicating that a promising therapeutic strategy for GBM is through inhibiting of SLC7A11 and PDIA3.