CISD2 knockdown suppresses gastric cancer and triggers ferroptosis

Knocking down the protein CISD2 slows the growth of gastric cancer cells and pushes them into ferroptosis, an iron-dependent form of cell death, according to a study published in Biology Direct on 15 October 2026. The work, led by Wenxin Zheng, Yue Cai, Tonghan Chang, Yuqing Niu, Feng Li and Biyun Zhang, positions CISD2 as a potential molecular target for gastric cancer therapy.

The researchers first established that CISD2, also known as CDGSH iron sulfur domain 2, is significantly upregulated in gastric cancer tissues. Preliminary analyses had revealed altered expression of the protein in gastric cancer samples, but its functional role in the disease, particularly in relation to ferroptosis, had remained unexplored before this study.

In laboratory experiments with gastric cancer cells, reducing CISD2 levels markedly inhibited three hallmark cancer behaviors: proliferation, migration and invasion. The effect was consistent across the in vitro models the team examined, supporting a pro-tumorigenic role for the protein in this cancer type.

The mechanistic core of the finding lies in ferroptosis, a regulated form of cell death driven by lipid peroxidation and dependent on iron. When the researchers knocked down CISD2, the gastric cancer cells underwent ferroptosis. This cell death was accompanied by downregulation of GPX4, an enzyme that normally protects cells by detoxifying lipid peroxides, and by inhibition of the mTOR/SREBF1/SCD1 signaling axis, a pathway linked to lipid metabolism.

To test whether the mTOR branch of that axis was causally involved, the team used MHY1485, a chemical activator of mTOR. Treating the CISD2-deficient cells with MHY1485 reversed the induced ferroptosis, providing further evidence that mTOR signaling participates in the ferroptosis triggered by CISD2 loss.

The findings were not confined to cell culture. In mouse xenograft experiments, in which human cancer cells are grown as tumors in animals, CISD2 knockdown significantly suppressed gastric cancer tumor growth, confirming that the anti-tumor effect observed in vitro extends to tumor formation in vivo.

The authors conclude that CISD2 plays a pro-tumorigenic role in gastric cancer and that its knockdown suppresses disease progression while inducing ferroptosis, concomitant with inhibition of the mTOR/SREBF1/SCD1 axis and downregulation of GPX4. On the basis of these results, they suggest that CISD2 represents a potential molecular target for gastric cancer therapy.

Gastric cancer remains a major global health challenge, with diverse risk factors and etiologies, strong invasiveness and frequent diagnosis at advanced stages, which the authors cite as the background motivating the search for new molecular targets. Ferroptosis has been extensively studied as an intrinsic tumor suppression mechanism, and the new study adds CISD2 to the growing list of proteins that appear to regulate it in cancer cells.

As with all preclinical work, the results come from cell culture and animal xenograft models, and the study does not report tests in human patients. The article was published as an open-access, peer-reviewed accepted manuscript, a version that is citable but subject to further edits before the final Version of Record appears. Whether targeting CISD2 can translate into a clinical strategy for gastric cancer will require further research beyond the scope of this study.

Subject of Research: The role of CISD2 in gastric cancer progression and ferroptosis

Article Title: CISD2 knockdown suppresses gastric cancer progression and induces ferroptosis associated with mTOR/SREBF1/SCD1 axis inhibition and GPX4 downregulation

Article References: Zheng, W., Cai, Y., Chang, T., Niu, Y., Li, F., & Zhang, B. (2026). CISD2 knockdown suppresses gastric cancer progression and induces ferroptosis associated with mTOR/SREBF1/SCD1 axis inhibition and GPX4 downregulation. Biology Direct. https://doi.org/10.1186/s13062-026-01009-6

Image Credits: AI Generated

DOI: 10.1186/s13062-026-01009-6

Keywords: CISD2, gastric cancer, ferroptosis, GPX4, mTOR, SREBF1, SCD1, lipid peroxidation, xenograft, tumor suppression, MHY1485, cell death