2. Academic Validation
  3. PDIA3 Inhibition Facilitates Sensitivity of IKE-Induced Ferroptosis via STAT3/LCN2 Axis to Improve Glioblastoma Therapy

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

  • Adv Sci (Weinh). 2025 Dec 14:e14191. doi: 10.1002/advs.202514191.
Jie Zhang 1,  Wei Wang 2,  Xin Liu 1 3,  Peifen Lu 3 4,  Xinjing Liu 3 4,  Qiucheng Nie 3 4,  Siyuan Xin 2,  Hong Li 3 4,  Donglin Yu 5,  Xinyue Zhang 3 4,  Kailong Li 5,  Xiaomin Han 2,  Shuping Zhang 1 3,  Wei Chong 3 6,  Lili Sun 3 4,  Wei Li 7,  Tao Xin 8,  Jin Jiao 3 4,  Qiang Ma 2,  Yiju Wei 3 4 8
Affiliations

Affiliations

  • 1 Biomedical Sciences College & Shandong Medicinal Biotechnology Center, Shandong First Medical University & Shandong Academy of Medical Science, Jinan, Shandong, 250117, China.
  • 2 Cancer Biology Institute, Baotou Medical College, Inner Mongolia Autonomous Region, Baotou, 014040, China.
  • 3 Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Science, Jinan, Shandong, 250117, China.
  • 4 School of Life Science, Shandong First Medical University & Shandong Academy of Medical Science, Tai'an, Shandong, 271016, China.
  • 5 Department of Biochemistry and Biophysics, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
  • 6 Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250117, China.
  • 7 Division of Hematology and Oncology, Department of Pediatrics, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, 17033, USA.
  • 8 Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, 250117, China.
PMID: 41391030 DOI: 10.1002/advs.202514191
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.

Keywords

LCN2; NEDD4L; PDIA3; ferroptosis; glioblastoma.

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