Abstract
Lung cancer is one of the most common malignant tumors worldwide, seriously threatening human health. PAB (pseudolaric acid B), an extract of pseudolarix amabilis, has exhibited notable anticancer properties. Nevertheless, the molecular mechanisms underlying PAB-induced anticancer activities remain controversial in lung cancer especially. Herein we aim to investigate the role of IAPs in PAB-induced anticancer effects. PAB selectively inhibits the viability of lung cancer cells and downregulates the expression of IAPs. Transcriptomic analysis suggests that PAB induces lung cancer cells ferroptosis. PAB indeed promotes ferroptotic cell death since PAB enhances lipid oxidation and Fe2+ content. Interestingly, PAB markedly enhances Survivin expression. Suppression of Survivin abolishes PAB-induced ferroptosis. PAB significantly strengthens JNK and ERK kinase activities. We further demonstrate suppression of JNK/ERK reversed PAB-mediated-cytotoxicity, meanwhile restores the expression of Survivin and ferroptosis-related proteins. Consistently, xenograft tumor model results also support that PAB induces ferroptosis through Survivin upregulation. Collectively, we demonstrate PAB induces ferroptosis in lung cancer cells in vivo and in vitro depending on JNK and ERK-mediated Survivin upregulation, providing novel insight for clinical administration of PAB in lung cancer.
Data availability
Genes related to ferroptosis are available on the FerrDb portal (http://www.zhounan.org/ferrdb/current/).The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2017) in BIG Data Center (Nucleic Acids Res 2017), Beijing Institute of Genomics (BIG), Chinese Academy of Sciences, under accession numbers HRA013555 that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human/.The data generated in the present study may be requested from the corresponding author.
Abbreviations
- AMPK:
-
adenosine 5’-monophosphate (AMP)-activated protein kinase
- Bax:
-
Bcl2-associated X protein
- Bcl2:
-
B-cell lymphoma 2
- CQ:
-
chloroquine
- CDK1:
-
cyclin-dependent kinases
- c-IAP1:
-
cellular inhibitor of apoptosis 1
- c-IAP2:
-
cellular inhibitor of apoptosis 2
- DFO:
-
deferoxamine
- ERK:
-
extracellular regulated protein kinases
- GPX4:
-
glutathione peroxidase 4
- HSP60:
-
heat shock protein 60
- IAPs:
-
inhibitor of apoptosis proteins
- IHC:
-
immunohistochemistry
- JNK:
-
c-Jun N-terminal kinase
- KEGG:
-
Kyoto Encyclopedia of Genes and Genomes
- MMP:
-
mitochondrial membrane potential
- MAPKs:
-
mitogen-activated protein kinase
- NAIP:
-
NLR family apoptosis inhibitory protein
- NCOA4:
-
nuclear Receptor Coactivator 4
- NSCLC:
-
non-small cell lung cancer
- PAB:
-
pseudolaric acid B
- PARP:
-
poly ADP-ribose polymerase
- RCD:
-
non-apoptotic regulated cell death
- ROS:
-
reactive oxygen species
- SLC7A11:
-
solute carrier family 7 member 11
- TCM:
-
traditional Chinese Medicine
- XIAP:
-
X-linked inhibitor of apoptosis protein
- 4-HNE:
-
4-Hydroxynonenal
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Acknowledgements
We are grateful for the technical support provided by the instrument sharing platform of Kunming Medical University and Yunnan University of Traditional Chinese Medicine.We thank Dr.Yasir Hameed and Dr.Mirza Imran Shahzad for their assistance with experimental work and data curation.
Funding
This work are supported by Yunnan Applied Basic Research Program (202201AT070043); National Natural Science Foundation of China (82460562, 82160581, 81560429); Yunnan Health training project of high level talents (D-2024001), 535 High Talent Project of First Affiliated Hospital of Kunming Medical University (2022535Q02); Yunnan Revitalization Talent Support Program, Yunnan Science Foundation of China (2019FF002(-011)); Yunnan Key Laboratory of Organ Transplantation (202449CE340016); The National Administration of Traditional Chinese Medicine High-level Key Discipline Construction Project “Dai Medicine”.
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Yuqiong Li and Changping Yu wrote the original manuscript text and Ruifen Sun and Shaoqing Shi review and editing the original manuscript text and Buqing Sai provide financial support. All authors reviewed the manuscript.
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All animal experiments were conducted in accordance with the ARRIVE guidelines and were approved by the Animal Experiment Ethics Committee of Kunming Medical University Laboratory Animal (approval number: kmmu20230490). Euthanasia was performed by intraperitoneal injection of pentobarbital sodium (150 mg/kg)29,30. All procedures were carried out by trained personnel to ensure animal welfare and minimize suffering.
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Li, Y., Yu, C., Yang, S. et al. Pseudolaric acid B promotes lung cancer cells ferroptosis depending on JNK/ERK-mediated upregulation of survivin. Sci Rep (2026). https://doi.org/10.1038/s41598-026-36423-3
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DOI: https://doi.org/10.1038/s41598-026-36423-3