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PDHA1 enhances resistance to ferroptosis in anoikis-resistant prostate cancer by upregulating AIFM2
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  • Published: 23 February 2026

PDHA1 enhances resistance to ferroptosis in anoikis-resistant prostate cancer by upregulating AIFM2

  • Yukun Cong1 na1,
  • Kang Chen1 na1,
  • Yunjie Ju1 na1,
  • Qingliu He1,2,
  • Chunyu Liu1,
  • Jiawei Chen1,
  • Fang Lv1,
  • Jinyu Chen1,
  • Haoran Li1,
  • Liang Chen1 &
  • …
  • Yarong Song  ORCID: orcid.org/0000-0003-0032-813X1 

Cell Death Discovery , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Extracellular matrix
  • Prostate cancer

Abstract

Cells that detach from the extracellular matrix (ECM) undergo various forms of cell death, including ferroptosis. Previous studies have demonstrated that prostate cancer (PCa) cells undergo ferroptosis following ECM detachment, and resistance to ferroptosis may facilitate tumor metastasis. Pyruvate dehydrogenase E1 alpha 1 (PDHA1) has been identified as a key regulator in the progression of several malignancies; however, its role in ferroptosis and prostate cancer metastasis remains unclear. In this study, anoikis resistance (AnoR) prostate cancer cells exhibited a substantial increase in PDHA1 expression, which enhanced their survival and metastatic potential by increasing resistance to ferroptosis. Mechanistically, nuclear PDHA1 in AnoR cells facilitated histone H3 lysine 9 acetylation (H3K9Ac) that significantly accumulated at the promoter region of peroxisome proliferator-activated receptor alpha (PPARA), thereby upregulating its expression. PPARA, in turn, activated the transcription of apoptosis-inducing factor mitochondria-associated 2 (AIFM2), whose upregulation inhibited ferroptosis in AnoR prostate cancer cells. This study demonstrates that PDHA1 expression is found to be elevated in primary tumors from patients with metastatic prostate cancer. Additionally, the aberrant overexpression of PDHA1 in AnoR prostate cancer cells upregulates PPARA and AIFM2 expression through nuclear translocation, collectively suppressing ferroptosis and promoting metastasis. These findings reveal a novel role for PDHA1 in mediating ferroptosis resistance during ECM detachment and provide a potential therapeutic target for prostate cancer treatment.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China no. 82103610 to YRS.

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Author notes

  1. These authors contributed equally: Yukun Cong, Kang Chen, Yunjie Ju.

Authors and Affiliations

  1. Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Yukun Cong, Kang Chen, Yunjie Ju, Qingliu He, Chunyu Liu, Jiawei Chen, Fang Lv, Jinyu Chen, Haoran Li, Liang Chen & Yarong Song

  2. Department of Urology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China

    Qingliu He

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Contributions

YKC: Writing original draft, Formal analysis, Data curation, Conceptualization. KC: Visualization, Formal analysis. YJJ: Visualization. CYL, QLH, and JWC: methodology, Writing—review & editing. FL, JYC: Formal analysis. HRL Visualization, Supervision. LC: Investigation. YRS: funding acquisition, Project administration. All authors read and approved the final paper.

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Correspondence to Haoran Li, Liang Chen or Yarong Song.

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Cong, Y., Chen, K., Ju, Y. et al. PDHA1 enhances resistance to ferroptosis in anoikis-resistant prostate cancer by upregulating AIFM2. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-02958-7

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  • Received: 09 June 2025

  • Revised: 12 December 2025

  • Accepted: 09 February 2026

  • Published: 23 February 2026

  • DOI: https://doi.org/10.1038/s41420-026-02958-7

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