Shikonin triggers apoptosis in lung adenocarcinoma through the FHL2-FOXO1 signaling axis
4 affiliations
- 1Weinan Central Hospital
- 2Second Affiliated Hospital, Dalian Medical University
- 3Department of Thoracic Surgery, First Affiliated Hospital of Dalian Medical University
- 4College of Pharmacy, Dalian Medical University
Abstract
Background FHL2 is an oncogenic scaffold protein that is overexpressed in lung adenocarcinoma (LUAD), making it a promising therapeutic target. SHK, a natural naphthoquinone, exhibits antitumor activity, but its molecular mechanism in LUAD, particularly its relationship with FHL2, remains unclear. Aim of this study The present study aimed to define the effects of SHK on NSCLC and identify the potential underlying molecular mechanisms. Methods The anti-tumor effects of SHK were evaluated in LUAD cell lines (A549andH1299) and a patient-derived xenograft (PDX) model using CCK-8, colony formation, Transwell, and flow cytometry assays. Integrated proteomics, bioinformatics, molecular docking, and cellular thermal shift assays (CETSAs) were employed to identify the direct target of SHK. The underlying mechanism was investigated through co-immunoprecipitation (Co-IP), Western blotting, qRT-PCR, cycloheximide (CHX) chase assays, and immunofluorescence/immunohistochemiscal (IF/IHC) staining. Results In both in vitro and PDX models, SHK potently inhibited LUAD growthand metastasisand induced cell death. At the molecular level, FHL2 was identified as a direct target of SHK. The direct binding of SHK to FHL2 promoted its proteasomal degradation, thereby disrupting the FHL2-FOXO1 complex. The dissociation of this complex increased FOXO1 acetylation and promoted its nuclear translocation, leading to the subsequent activation of the caspase cascade and apoptosis. Conclusion Our findings indicate a novel signaling pathway through which SHK inhibits LUAD: by directly targeting FHL2 for degradation, SHK disrupts the FHL2-FOXO1 complex, which activates FOXO1-mediated transcription and triggers apoptosis. This study not only provides mechanistic insight into the antitumor function of SHK but also identifies the FHL2-FOXO1 axis as a potential therapeutic target for LUAD.
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BibTeX
@article{chen2026shikonin,
title = {{Shikonin triggers apoptosis in lung adenocarcinoma through the FHL2-FOXO1 signaling axis}},
author = {Shiqun Chen and Meirong Zhou and Wen Zhang and Jiyong Zhong and Wenqian Han and Zhaoxuan Wang and Shiqing Wang and Chundong Gu and Zhenlong Yu and Shilei Zhao},
journal = {Journal of Translational Medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08767-x},
url = {https://doi.org/10.1186/s12967-026-08767-x},
note = {CC BY},
}
RIS
TY - JOUR
TI - Shikonin triggers apoptosis in lung adenocarcinoma through the FHL2-FOXO1 signaling axis
AU - Shiqun Chen
AU - Meirong Zhou
AU - Wen Zhang
AU - Jiyong Zhong
AU - Wenqian Han
AU - Zhaoxuan Wang
AU - Shiqing Wang
AU - Chundong Gu
AU - Zhenlong Yu
AU - Shilei Zhao
PY - 2026
DA - 2026/08/01
JO - Journal of Translational Medicine
DO - 10.1186/s12967-026-08767-x
UR - https://doi.org/10.1186/s12967-026-08767-x
AB - Background FHL2 is an oncogenic scaffold protein that is overexpressed in lung adenocarcinoma (LUAD), making it a promising therapeutic target. SHK, a natural naphthoquinone, exhibits antitumor activity, but its molecular mechanism in LUAD, particularly its relationship with FHL2, remains unclear. Aim of this study The present study aimed to define the effects of SHK on NSCLC and identify the potential underlying molecular mechanisms. Methods The anti-tumor effects of SHK were evaluated in LUAD cell lines (A549andH1299) and a patient-derived xenograft (PDX) model using CCK-8, colony formation, Transwell, and flow cytometry assays. Integrated proteomics, bioinformatics, molecular docking, and cellular thermal shift assays (CETSAs) were employed to identify the direct target of SHK. The underlying mechanism was investigated through co-immunoprecipitation (Co-IP), Western blotting, qRT-PCR, cycloheximide (CHX) chase assays, and immunofluorescence/immunohistochemiscal (IF/IHC) staining. Results In both in vitro and PDX models, SHK potently inhibited LUAD growthand metastasisand induced cell death. At the molecular level, FHL2 was identified as a direct target of SHK. The direct binding of SHK to FHL2 promoted its proteasomal degradation, thereby disrupting the FHL2-FOXO1 complex. The dissociation of this complex increased FOXO1 acetylation and promoted its nuclear translocation, leading to the subsequent activation of the caspase cascade and apoptosis. Conclusion Our findings indicate a novel signaling pathway through which SHK inhibits LUAD: by directly targeting FHL2 for degradation, SHK disrupts the FHL2-FOXO1 complex, which activates FOXO1-mediated transcription and triggers apoptosis. This study not only provides mechanistic insight into the antitumor function of SHK but also identifies the FHL2-FOXO1 axis as a potential therapeutic target for LUAD.
SN - 1479-5876
ER -