BDH2 Inhibits Lung Adenocarcinoma Metastasis by Promoting Ferroptosis

Qiao Yang; Lin Tian; Xiaodong Chen; Xiong Mei; Yongli Nie; Jun Chen

doi:10.2478/aite-2026-0012

.blurhash-client-img { display: none !important; }

BDH2 Inhibits Lung Adenocarcinoma Metastasis by Promoting Ferroptosis

Archivum Immunologiae et Therapiae Experimentalis

Volume 74 (2026): Issue 1 (January 2026)

By: Qiao Yang, Lin Tian, Xiaodong Chen, Xiong Mei, Yongli Nie and Jun Chen

Open Access

|Apr 2026

Abstract

To investigate the role of 3-hydroxybutyrate dehydrogenase 2 (BDH2) in regulating ferroptosis and its impact on the metastasis of lung adenocarcinoma (LUAD). Expression levels of BDH2 were modulated in LUAD cell lines (A549, PC9) using pcDNA-BDH2 plasmid transfection. Cell motility was assessed by Transwell assays, while ferroptosis-associated markers, including Fe²⁺, malondialdehyde (MDA), lipid reactive oxygen species (ROS), ACSL4, and GPX4, were evaluated by biochemical assays, flow cytometry, and Western blotting. The involvement of the Nrf2/HO-1 signaling axis was analyzed by Western blotting and RT-qPCR. Furthermore, a xenograft mouse model was established to confirm the effect of BDH2 on tumor progression and metastasis in vivo. Overexpression of BDH2 significantly inhibited LUAD cell migration and invasion. BDH2 upregulation enhanced ferroptosis, effects that were reversed by the ferroptosis inhibitor Fer-1. Mechanistically, BDH2 suppressed the activation of the Nrf2/HO-1 pathway, thereby enhancing sensitivity to ferroptosis. In vivo, BDH2 overexpression markedly reduced tumor growth and metastasis in nude mice, while inhibition of ferroptosis attenuated these effects. BDH2 suppresses metastasis in LAUD by promoting ferroptosis via suppression of the Nrf2/HO-1 pathway, highlighting BDH2 as a potential therapeutic target for LUAD.

References

Cao JY, Dixon SJ (2016) Mechanisms of ferroptosis. Cell Mol Life Sci 73:2195–2209. https://doi.org/10.1007/s00018-016-2194-1
Search in Google Scholar Back to article
Chen Y, Zhou Y, Ren R et al. (2024) Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma. J ImmunoTher Cancer 12:e008811. https://doi.org/10.1136/jitc-2024-008811
Search in Google Scholar Back to article
Cui Y, Zhang Y, Zhao X et al. (2021) ACSL4 exacerbates ischemic stroke by promoting ferroptosis-induced brain injury and neuroinflammation. Brain Behav Immun 93:312–321. https://doi.org/10.1016/j.bbi.2021.01.003
Search in Google Scholar Back to article
Denisenko TV, Budkevich IN, Zhivotovsky B (2018) Cell death-based treatment of lung adenocarcinoma. Cell Death Dis 9:117. https://doi.org/10.1038/s41419-017-0063-y
Search in Google Scholar Back to article
Feng Q, Yang Y, Qiao Y et al. (2023) Quercetin ameliorates diabetic kidney injury by inhibiting ferroptosis via activating Nrf2/HO-1 signaling pathway. Am J Chin Med 51:997–1018. https://doi.org/10.1142/S0192415X23500465
Search in Google Scholar Back to article
Lei G, Zhuang L, Gan B (2022) Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer 22:381–396. https://doi.org/10.1038/s41568-022-00459-0
Search in Google Scholar Back to article
Li Y, Li N, Xi L et al. (2024) Predictive value of the BDH2-MN2 nomogram model for prognosis at 3 months after receiving intravenous thrombolysis in patients with acute ischemic stroke. Arch Med Sci 20:1143–1152. https://doi.org/10.5114/aoms/176740
Search in Google Scholar Back to article
Liu JZ, Hu YL, Feng Y et al. (2020) BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer. J Exp Clin Cancer Res 39:123. https://doi.org/10.1186/s13046-020-01620-z
Search in Google Scholar Back to article
Lovly CM (2022) Expanding horizons for treatment of early-stage lung cancer. N Engl J Med 386:2050–2051. https://doi.org/10.1056/NEJMe2203330
Search in Google Scholar Back to article
Rizzollo F, Escamilla-Ayala A, Fattorell N et al. (2025) Agostinis, BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states. Nat Metab 7:1851–1870. https://doi.org/10.1038/s42255-025-01352-4
Search in Google Scholar Back to article
Scindia Y, Mehrad B, Morel L (2022) Labile iron accumulation augments T follicular helper cell differentiation. J Clin Invest 132:e159472. https://doi.org/10.1172/JCI159472
Search in Google Scholar Back to article
Seah C, Karabacak M, Margetis K (2025) Transcriptomic imputation identifies tissue-specific genes associated with cervical myelopathy. Spine J 25:588–596. https://doi.org/10.1016/j.spinee.2024.10.014
Search in Google Scholar Back to article
Tandon R, Levey AI, Lah JJ (2023) Machine learning selection of most predictive brain proteins suggests role of sugar metabolism in Alzheimer’s disease. J Alzheimers Dis 92:411–424. https://doi.org/10.3233/JAD-22068
Search in Google Scholar Back to article
Wei X, Li X, Hu S et al. (2023) Regulation of ferroptosis in lung adenocarcinoma. Int J Mol Sci 24:14614. https://doi.org/10.3390/ijms241914614
Search in Google Scholar Back to article
Wei Z, Yu H, Zhao H et al. (2024) Broadening horizons: Ferroptosis as a new target for traumatic brain injury. Burns Trauma 12:tkad051. https://doi.org/10.1093/burnst/tkad051
Search in Google Scholar Back to article
Wenqiao, Zang, Tao, Wang, Yuanyuan, Wang et al. Knockdown of long non-coding RNA TP73-AS1 inhibits cell proliferation and induces apoptosis in esophageal squamous cell carcinoma. Oncotarget, 2016, 7:19960–74.
Search in Google Scholar Back to article
Wu J, Li H, Hu F et al. (2022) Stevioside attenuates osteoarthritis via regulating Nrf2/HO-1/NF-kappaB pathway. J Orthop Translat 38:190–202. https://doi.org/10.1016/j.jot.2022.05.005
Search in Google Scholar Back to article
Wu XT, Wang YH, Cai XY et al. (2021) RNF115 promotes lung adenocarcinoma through Wnt/beta-catenin pathway activation by mediating APC ubiquitination. Cancer Metab 9:7. https://doi.org/10.1186/s40170-021-00243-y
Search in Google Scholar Back to article
Xu Y, Zhang K, Ye Z et al. (2025) Nanomedicine initiates ferroptosis for enhanced lung cancer therapy. Drug Deliv 32:2527752. https://doi.org/10.1080/10717544.2025.2527752
Search in Google Scholar Back to article
Yi, Luan, Yang, Yang, Ying, Luan et al. Targeting ferroptosis and ferritinophagy: new targets for cardiovascular diseases. J Zhejiang Univ Sci B, 2024, 25:1–22.
Search in Google Scholar Back to article
Zhu W, Zhang Y, Yang L et al. (2025) Construction of a lung adenocarcinoma prognostic model based on KEAP1/NRF2/HO 1 mutation mediated upregulated genes and bioinformatic analysis. Oncol Lett 29:155. https://doi.org/10.3892/ol.2025.14902
Search in Google Scholar Back to article
Zuo L, Zou X, Ge J et al. (2025) The Nrf2-HMOX1 pathway as a therapeutic target for reversing cisplatin resistance in non-small cell lung cancer via inhibiting ferroptosis. Cell Death Discov 11:287. https://doi.org/10.1038/s41420-025-02564-z
Search in Google Scholar Back to article

Articles in this issue

DOI: https://doi.org/10.2478/aite-2026-0012 | Journal eISSN: 1661-4917

Journal RSS Feed

Language: English

Submitted on: Oct 14, 2025

Accepted on: Feb 6, 2026

Published on: Apr 9, 2026

Published by: Hirszfeld Institute of Immunology and Experimental Therapy

In partnership with: Paradigm Publishing Services

Publication frequency: 1 issue per year

Keywords:

BDH2,

Related subjects:

Basic medical science,

Biochemistry,

Immunology,

Clinical medicine,

Clinical medicine, other,

Clinical chemistry

© 2026 Qiao Yang, Lin Tian, Xiaodong Chen, Xiong Mei, Yongli Nie, Jun Chen, published by Hirszfeld Institute of Immunology and Experimental Therapy
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

Volume 74 (2026): Issue 1 (January 2026)