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  3. Buzhong yiqi decoction improves cisplatin resistance in non-small cell lung cancer by inhibiting PCBP1 to activate the ferritinophagy-mediated ferroptosis pathway

Buzhong yiqi decoction improves cisplatin resistance in non-small cell lung cancer by inhibiting PCBP1 to activate the ferritinophagy-mediated ferroptosis pathway

  • J Ethnopharmacol. 2025 Jul 20;353(Pt A):120317. doi: 10.1016/j.jep.2025.120317.
Yue-Tong Liu 1,  Hao-Ran Cai 2,  He Li 3,  Qi-Rui Mu 4,  Jing-Yi Huang 5,  Yuan Gao 6
Affiliations

Affiliations

  • 1 College of Integrated Traditional Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China; National and Local Joint Engineering Laboratory for Integrated Chinese and Western Medicine Prevention and Treatment Technology on Cardio-Brain Diseases, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China; Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China. Electronic address: 1047928253@qq.com.
  • 2 College of Integrated Traditional Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China; National and Local Joint Engineering Laboratory for Integrated Chinese and Western Medicine Prevention and Treatment Technology on Cardio-Brain Diseases, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China; Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China. Electronic address: 2949210868@qq.com.
  • 3 College of Integrated Traditional Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China; National and Local Joint Engineering Laboratory for Integrated Chinese and Western Medicine Prevention and Treatment Technology on Cardio-Brain Diseases, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China; Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China. Electronic address: 1197386342@qq.com.
  • 4 College of Integrated Traditional Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China; National and Local Joint Engineering Laboratory for Integrated Chinese and Western Medicine Prevention and Treatment Technology on Cardio-Brain Diseases, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China; Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China. Electronic address: 810198976@qq.com.
  • 5 College of Integrated Traditional Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China; National and Local Joint Engineering Laboratory for Integrated Chinese and Western Medicine Prevention and Treatment Technology on Cardio-Brain Diseases, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China; Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China. Electronic address: 840890363@qq.com.
  • 6 College of Integrated Traditional Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China; National and Local Joint Engineering Laboratory for Integrated Chinese and Western Medicine Prevention and Treatment Technology on Cardio-Brain Diseases, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China; Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China. Electronic address: gaoyuan.laury@163.com.
PMID: 40695404 DOI: 10.1016/j.jep.2025.120317
Abstract

Ethnopharmacological relevance: Traditional Chinese Medicine (TCM) holds that lung Cancer primarily results from deficiency of healthy qi (vital energy) and insufficiency of spleen qi. Buzhong Yiqi Decoction (BZYQD) is a classic formulation based on the 'reinforcing earth to generate metal' principle in traditional Chinese medicine. Currently, it is commonly used to treat advanced-stage lung Cancer and has been proven to significantly improve cisplatin resistance in A549/DDP cells. It can upregulate the expression levels of typical Ferroptosis markers such as ROS and downregulate the expression of key Ferroptosis regulatory protein GPX4. However, its relationship with Ferroptosis remains unclear.

Aim of the study: The aim of this study aims to confirm the relationship between BZYQD improving cisplatin resistance and Ferroptosis in A549/DDP cells, and to elucidate its potential mechanism.

Materials and methods: Low-, medium-, and high-dose BZYQD-mediating serum (BZYQD-MS) is prepared from rats to screen the optimal intervention concentration of BZYQD. PCR Array kit is used to screen core regulatory genes of BZYQD in improving cisplatin resistance of A549/DDP among 90 ferroptosis-related genes. The effects of BZYQD on cisplatin sensitivity were evaluated using the Cell Counting Kit-8 (CCK-8) proliferation and cytotoxicity assay. To investigate BZYQD-mediated regulation of Ferroptosis, we performed: ultrastructural analysis of mitochondria by transmission electron microscopy (TEM); quantification of the Ferroptosis marker GPX4 by Western blot; and measurement of Ferroptosis biomarkers including lipid Reactive Oxygen Species (ROS) using C11-BODIPY 581/591 fluorescent probe, Fe2+ with an iron assay kit, and malondialdehyde (MDA) levels with a lipid peroxidation assay kit. The impact of BZYQD on the ferritinophagy pathway was assessed by Western blot analysis of ferritinophagy-related proteins (FTH1, NCOA4, LC3Ⅱ/Ⅰ, and p62).Additionally, PCBP1 overexpression is induced by Cell Transfection, and the expression of PCBP1 is examined by Western blot to verify the effect of BZYQD on PCBP1 and its interaction in the ferritinophagy pathway and Ferroptosis.

Results: (1)BZYQD effectively reverses cisplatin resistance in A549/DDP cells, with the medium dose showing optimal activity. (2)BZYQD activates Ferroptosis to overcome cisplatin resistance in A549/DDP cells, as confirmed by ferrostatin-1 inhibition experiments. (3)PCBP1 is one of the most crucial ferroptosis-related genes associated with BZYQD-mediated reversal of cisplatin resistance in A549/DDP cells. (4)BZYQD suppresses PCBP1 to activate the ferritinophagy pathway, thereby promoting Ferroptosis and restoring cisplatin sensitivity in A549/DDP cells.

Conclusions: Buzhong Yiqi Decoction improves cisplatin resistance in non-small cell lung Cancer by inhibiting PCBP1 to activate the ferritinophagy-mediated Ferroptosis pathway.

Keywords

Buzhong Yiqi decoction; Cisplatin resistance; Ferritinophagy; Non-small cell lung cancer; PCBP1; ferroptosis.

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