2. Academic Validation
  3. The alkylglycerone phosphate synthase sustains the resistance of gastric cancer cells to ferroptosis induced by Apatinib

The alkylglycerone phosphate synthase sustains the resistance of gastric cancer cells to ferroptosis induced by Apatinib

  • Gastric Cancer. 2025 Jul;28(4):579-597. doi: 10.1007/s10120-025-01610-0.
Minghao Wang # 1,  Qiyuan An # 2,  Zhiwei Li 1,  Zhicheng Huang 1,  Kaihua Huang 1,  Guoxin Li 1,  Qiang Ma 2,  Liying Zhao 3
Affiliations

Affiliations

  • 1 Department of General Surgery and Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
  • 2 Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of General Surgery and Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China. zlyblue11@163.com.
  • # Contributed equally.
PMID: 40186794 DOI: 10.1007/s10120-025-01610-0
Abstract

Background: Apatinib is a targeted therapy used in the treatment of advanced gastric Cancer. However, many gastric Cancer patients develop resistance to Apatinib, and the mechanisms underlying this resistance remain unclear. Previous studies have shown that Apatinib can induce Ferroptosis in gastric Cancer cells. More recent research suggests that polyunsaturated ether Phospholipids are closely associated with tumor cell sensitivity to Ferroptosis, and may represent key molecules involved in the resistance of tumor cells to Ferroptosis.

Methods: We established Apatinib-resistant gastric Cancer cell lines and assessed their tolerance to Ferroptosis. We identified key Enzymes responsible for the Ferroptosis tolerance observed in drug-resistant cells using lipidomics and transcriptomics analysis. Molecular and biological experiments were conducted to elucidate the molecular mechanisms underlying Apatinib resistance mediated by Ferroptosis tolerance in gastric Cancer cells.

Results: Apatinib resistance is closely linked to Ferroptosis resistance, which is driven by a reduction in the levels of polyunsaturated ether phospholipids-phospholipids that are particularly susceptible to oxidation and induce Ferroptosis. The downregulation of key Enzymes involved in polyunsaturated ether phospholipid synthesis, such as AGPS, mediates tolerance to both Ferroptosis and Apatinib in gastric Cancer cells, both in vitro and in vivo. Mechanistically, the expression of AGPS in tumor cells is regulated by the transcription factor ELK1. Drug-resistant cells acquire Apatinib tolerance by downregulating both ELK1 and AGPS expression.

Conclusions: Apatinib-resistant gastric Cancer cells exhibit reduced expression of the transcription factor ELK1, which regulates the expression of AGPS. This reduction contributes to the resistance and malignancy of gastric Cancer cells.

Keywords

AGPS; Apatinib; Ferroptosis; Gastric cancer; Polyunsaturated ether phospholipids.

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