2. Academic Validation
  3. Mechanism of Saikosaponin D in regulating ferroptosis in patient-derived lung adenocarcinoma organoids via upregulation of ATF3/CHOP/CHAC1 signaling

Mechanism of Saikosaponin D in regulating ferroptosis in patient-derived lung adenocarcinoma organoids via upregulation of ATF3/CHOP/CHAC1 signaling

  • Sci Rep. 2026 Jan 31;16(1):2513. doi: 10.1038/s41598-025-27251-y.
Jia Li # 1 2,  Qiong Ma # 1,  Chunxia Huang # 1,  Xiao Zeng 1,  Jiawei He 1,  Liting You 3,  Xiang Zhuang 4,  Ping Xiao 4,  Fengming You 1 2,  Yifeng Ren 5 6,  Chuan Zheng 7 8 9
Affiliations

Affiliations

  • 1 Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
  • 2 TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
  • 3 Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 4 Department of Thoracic Surgery, School of Medicine, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, 610041, China.
  • 5 Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China. [email protected].
  • 6 TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China. [email protected].
  • 7 Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China. [email protected].
  • 8 TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China. [email protected].
  • 9 Sichuan Provincial Engineering Research Center of Innovative Re- development of Famous Classical Formulas, Tianfu TCM Innovation Harbour, Chengdu University of Traditional Chinese Medicine, Chengdu, 611930, China. [email protected].
  • # Contributed equally.
PMID: 41620478 DOI: 10.1038/s41598-025-27251-y
Abstract

Lung adenocarcinoma (LUAD) is associated with high morbidity and mortality, making the discovery of novel and effective drugs treatment crucial.This study aimed to identify and evaluate antitumor saponin monomers with better effects using patient-derived Organoid (PDO) models from patients with LUAD. We successfully constructed LUAD PDO models and confirmed their similarity to original tissues using immunohistochemistry and immu-nofluorescence staining. We performed drug sensitivity screening using the CCK-8 assay on five kinds of saponin monomers. saikosaponin D (SSD) was identified as having the highest antitumor potential and we then validated its efficacy. The antitumor mechanism of the saponin monomer was elucidated using RNA Sequencing and confirmed using flow cytometry, ferrous ion determi-nation, RT-qPCR, western blotting, molecular docking and drug affinity responsive target stability experiment. SSD exhibited concentration-dependent inhibition of PDO viability in LUAD and inhibited proliferation and mi-gration of A549 lung Cancer cells. Mechanistically, the results from the PDO and A549 cell ex-periments were consistent with those of the RNA Sequencing analysis, indicating that SSD upreg-ulated the ATF3/CHOP/CHAC1 pathway, triggered endoplasmic reticulum stress, and induced Ferroptosis. We demonstrate that SSD exerted stronger antitumor effects than cis-platin. These findings lay the groundwork for the potential application of SSD in the treatment of LUAD.

Keywords

Endoplasmic reticulum stress; Ferroptosis; Lung adenocarcinoma; Organoid; Saikosaponin D.

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