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Schisantherin A induces ferroptosis in non‑small cell lung cancer through activation of the YAP/ACSL4/TfR signaling pathway

  • Authors:
    • Wenxiang Zhu
    • Yeyang Chen
    • Xiangjian Wu
    • Xiaoyan Fu
    • Yongshi He
    • Yuxia Mo
    • Qinghua Zhu
    • Mingwen Tang
    • Zhiguang Zhai
  • View Affiliations / Copyright

    Affiliations: The Fourth Clinical Medical College, Department of Respiratory and Critical Care Medicine, Shenzhen Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, P.R. China, School of Chinese Medicine, Studies and Applications of Internal Chinese Medicines, Hong Kong Baptist University, Hong Kong, SAR, P.R. China, Institute of Basic Theory for Chinese Medicine, Basic Research Center for Prevention and Treatment of Viral Diseases with Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, P.R. China
    Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 24
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    Published online on: November 3, 2025
       https://doi.org/10.3892/mmr.2025.13734
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Abstract

Schisantherin A (Sch A), a compound derived from Schisandra chinensis, has anti‑inflammatory, antitumor, neuroprotective and antifibrotic properties. However, to the best of our knowledge, the role of Sch A in non‑small cell lung cancer (NSCLC) has not yet been reported. The purpose of the present study was to determine whether Sch A can prevent the development of NSCLC and to elucidate the underlying mechanisms involved. The results of the present study demonstrated that Sch A inhibited the viability of A549 and HCC827 cells. Furthermore, Sch A increased the intracellular Fe2+ level, reduced the mitochondrial membrane potential and depleted the glutathione content in lung cancer cells. These effects were reversed by the ferroptosis inhibitors ferrostatin‑1 and deferoxamine. Bioinformatics analysis and reverse transcription‑quantitative PCR results suggested that Sch A increased the mRNA levels of the transcription factor yes‑associated protein (YAP). Additionally, Sch A upregulated the expression of YAP and ferroptosis‑related proteins, including acyl‑CoA synthase long‑chain family member 4 (ACSL4) and transferrin receptor (TfR), in lung cancer cells. Silencing of YAP led to the downregulation of its downstream targets, ACSL4 and TfR, even in the presence of Sch A. In vivo, Sch A significantly inhibited subcutaneous tumor growth in nude mice. In conclusion, Sch A may activate the YAP/ACSL4/TfR signaling axis to induce ferroptosis in NSCLC cells, positioning it as a potential small‑molecule therapeutic agent for NSCLC.
View Figures

Figure 1

Lung cancer cell viability is
suppressed by Sch A in a concentration- and time-dependent manner.
Sch A decreased (A) A549 and (B) HCC827 cell viability in a
concentration-dependent manner, according to Cell Counting Kit-8
analysis. Sch A significantly reduced the viability of (C) A549 and
(D) HCC827 cells at 24, 48 and 72 h. ***P<0.001 vs. Con. Con,
control; Sch A, Schisantherin A; OD, optical density.

Figure 2

Sch A induces cell death and cell
cycle arrest in A549 and HCC827 cells. Sch A considerably increased
the death of (A) A549 and (B) HCC827 cells in comparison with the
control group, according to flow cytometric analysis. Compared with
Con, (C) A549 and (D) HCC827 cells presented a significant decrease
in the number of G2 + S-phase cells and a significant
increase in the number of G1-phase cells. Fer-1 and DFO
were able to significantly reverse the Sch A-induced decrease in
(E) A549 and (F) HCC827 cell viability, according to the results of
the Cell Counting Kit-8 analysis. *P<0.05, **P<0.01 and
***P<0.001 vs. Con; ##P<0.01 and
###P<0.001 vs. Sch A. DFO, deferoxamine; Con,
control; Sch A, Schisantherin A; Fer-1, ferrostatin-1; Nec-1,
necrostatin-1; 3-MA, 3-methyladenine.

Figure 3

In A549 and HCC827 cells, ferroptosis
inhibitors prevent Sch A-induced apoptosis. Fer-1 and DFO were
shown by JC-1 staining to reverse the Sch A-induced MMP reduction
in (A) A549 and (B) HCC827 cells (scale bar, 30 µm). Fer-1 and DFO
inhibited the Sch A-induced increase in MDA in (C) A549 and (D)
HCC827 cells. Fer-1 and DFO counteracted the Sch A-induced
reduction in GSH in (E) A549 and (F) HCC827 cells. Reverse
transcription-quantitative PCR analysis revealed that Fer-1 and DFO
reversed the Sch A-induced increase in Chac1 and ptgs2 levels in
(G) A549 and (H) HCC827 cells. *P<0.05, **P<0.01 and
***P<0.001 vs. Con; #P<0.05,
##P<0.01 and ###P<0.001 vs. Sch A. Con,
control; Chac1, glutathione-specific γ-glutamylcyclotransferase 1;
ptgs2, prostaglandin-endoperoxide synthase 2; Fer-1, ferrostatin-1;
DFO, deferoxamine; Sch A, Schisantherin A; MDA, malondialdehyde;
GSH, glutathione.

Figure 4

Sch A induces ferroptosis in lung
cancer cells by activating YAP signaling. (A) GeneCards
intersection analysis revealed 739 overlapping genes associated
with both ferroptosis and NSCLC. (B) Transcription factors among
the intersecting genes were analyzed to identify key node genes.
Reverse-transcription-quantitative PCR analysis revealed that Sch A
increased the mRNA expression levels of YAP1 in (C) A549 and (D)
HCC827 cells. Western blot analysis revealed that Sch A increased
the expression levels of TfR, ACSL4 and YAP in (E) A549 and (F)
HCC827 cells. *P<0.05 and **P<0.01 vs. Con. Con, control;
YAP, yes-associated protein; Sch A, Schisantherin A; TfR,
transferrin receptor; ACSL4, acyl-CoA synthase long-chain family
member 4; NSCLC, non-small cell lung cancer.

Figure 5

Silencing of YAP reverses Sch
A-induced ferroptosis. Western blot analysis showed that the
expression of YAP was decreased in (A) A549 and (B) HCC827 cells.
In (C) A549 and (D) HCC827 cells, si-YAP decreased the expression
of YAP and downstream signaling molecules. Fe2+
accumulation was induced by Sch A in (E) A549 and (F) HCC827 cells,
and the increase in Fe2+ was reversed by YAP silencing,
as demonstrated by FerroOrange staining (scale bar, 10 µm). After
silencing YAP, the Sch A-induced increase in Fe2+ and
MDA in (G) A549 and (H) HCC827 cells was reduced. *P<0.05,
**P<0.01 and ***P<0.001 vs. NC; ###P<0.001 vs.
Sch A. NC, negative control; YAP, yes-associated protein; Sch A,
Schisantherin A; si, small interfering RNA; MDA, malondialdehyde;
ACSL4, acyl-CoA synthase long-chain family member 4; TfR,
transferrin receptor.

Figure 6

In vivo, Sch A prevents the
formation of tumors in nude mice. Compared with Con, Sch A
inhibited (A) tumor mass and (B) volume in vivo in nude
mice. Sch A increased the (C) Fe2+ and (D) MDA contents
in nude mouse tumors. (E) Sch A diminished the GSH levels in the
tumors compared with those in the Con group. (F) Compared with
those in the Con group, Sch A induced the expression levels of YAP,
ACSL4 and TfR in the tumors of nude mice. *P<0.05 and
***P<0.001 vs. Con. Con, control; Sch A, Schisantherin A; MDA,
malondialdehyde; GSH, glutathione; YAP, yes-associated protein;
ACLS4, acyl-CoA synthase long-chain family member 4; TfR,
transferrin receptor.

Figure 7

Schematic diagram showing the
molecular mechanism by which Sch A suppresses NSCLC. Sch A,
Schisantherin A; NSCLC, non-small cell lung cancer; YAP,
yes-associated protein; ACSL4 acyl-CoA synthase long-chain family
member 4; TfR, transferrin receptor.
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Copy and paste a formatted citation
Spandidos Publications style
Zhu W, Chen Y, Wu X, Fu X, He Y, Mo Y, Zhu Q, Tang M and Zhai Z: Schisantherin A induces ferroptosis in non‑small cell lung cancer through activation of the YAP/ACSL4/TfR signaling pathway. Mol Med Rep 33: 24, 2026.
APA
Zhu, W., Chen, Y., Wu, X., Fu, X., He, Y., Mo, Y. ... Zhai, Z. (2026). Schisantherin A induces ferroptosis in non‑small cell lung cancer through activation of the YAP/ACSL4/TfR signaling pathway. Molecular Medicine Reports, 33, 24. https://doi.org/10.3892/mmr.2025.13734
MLA
Zhu, W., Chen, Y., Wu, X., Fu, X., He, Y., Mo, Y., Zhu, Q., Tang, M., Zhai, Z."Schisantherin A induces ferroptosis in non‑small cell lung cancer through activation of the YAP/ACSL4/TfR signaling pathway". Molecular Medicine Reports 33.1 (2026): 24.
Chicago
Zhu, W., Chen, Y., Wu, X., Fu, X., He, Y., Mo, Y., Zhu, Q., Tang, M., Zhai, Z."Schisantherin A induces ferroptosis in non‑small cell lung cancer through activation of the YAP/ACSL4/TfR signaling pathway". Molecular Medicine Reports 33, no. 1 (2026): 24. https://doi.org/10.3892/mmr.2025.13734
Copy and paste a formatted citation
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Spandidos Publications style
Zhu W, Chen Y, Wu X, Fu X, He Y, Mo Y, Zhu Q, Tang M and Zhai Z: Schisantherin A induces ferroptosis in non‑small cell lung cancer through activation of the YAP/ACSL4/TfR signaling pathway. Mol Med Rep 33: 24, 2026.
APA
Zhu, W., Chen, Y., Wu, X., Fu, X., He, Y., Mo, Y. ... Zhai, Z. (2026). Schisantherin A induces ferroptosis in non‑small cell lung cancer through activation of the YAP/ACSL4/TfR signaling pathway. Molecular Medicine Reports, 33, 24. https://doi.org/10.3892/mmr.2025.13734
MLA
Zhu, W., Chen, Y., Wu, X., Fu, X., He, Y., Mo, Y., Zhu, Q., Tang, M., Zhai, Z."Schisantherin A induces ferroptosis in non‑small cell lung cancer through activation of the YAP/ACSL4/TfR signaling pathway". Molecular Medicine Reports 33.1 (2026): 24.
Chicago
Zhu, W., Chen, Y., Wu, X., Fu, X., He, Y., Mo, Y., Zhu, Q., Tang, M., Zhai, Z."Schisantherin A induces ferroptosis in non‑small cell lung cancer through activation of the YAP/ACSL4/TfR signaling pathway". Molecular Medicine Reports 33, no. 1 (2026): 24. https://doi.org/10.3892/mmr.2025.13734
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