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<p>Natural killer (NK) cells play a crucial role in combating gastric cancer (GC). However, they undergo ferroptosis in the tumor microenvironment of GC, which weakens their antitumor effects. Exosomal circRNA influences GC progression. Previous studies have reported the cancer-promoting role of <i>circPDSS1</i> in GC, but whether it is involved in NK cell ferroptosis remains unclear. This study aimed to investigate the role of GC cell-derived exosomal <i>circPDSS1</i> in NK cell ferroptosis. A noncontact coculture system of GC cells (HGC-27, AGS, and MKN-45 cells) and human NK-92 cells was established, and humanized mouse and cell-derived xenograft (CDX) tumor models were constructed for joint investigation. Cell death and viability were assessed via flow cytometry, LDH release assays and CCK-8 assays; <i>circPDSS1</i> stability was determined by agarose gel electrophoresis and actinomycin D treatment; ferroptosis was determined by measuring lipid ROS, MDA, and Fe<sup>2+</sup> levels; and key molecular interactions were determined by performing dual-luciferase reporter assays and RIP and RNA pull-down experiments. CD56 and CD16 expression was reduced in clinical tumor tissues. <i>In vitro</i> experiments revealed that the proportion of 7-AAD<sup>+</sup> NK-92 cells cocultured with GC cells was significantly increased, accompanied by increased cell mortality and decreased IFN-γ and TNF-α secretion. Further studies revealed that <i>circPDSS1</i> expression was abnormally elevated in GC tissues and cells and was particularly enriched in MKN-45 cell-derived exosomes (Exos). Knockdown of <i>circPDSS1</i> alleviated MKN-45-Exo-induced cell damage; reduced lipid ROS, MDA, and Fe<sup>2+</sup> levels in NK-92 cells; and delayed tumor progression. Furthermore, a ferroptosis inhibitor suppressed <i>circPDSS1</i> overexpression-induced cell death. Mechanistically, <i>circPDSS1</i> sponged <i>miR-142-3p</i> to upregulate ACSL4 expression, promoting NK cell ferroptosis. Exosomal <i>circPDSS1</i> derived from GC cells contributes to NK cell ferroptosis by sponging <i>miR-142-3p</i> to increase ACSL4 expression and exacerbate GC.</p>

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Exosomal circPDSS1 Derived From Gastric Cancer Cells Promotes Natural Killer Cell Ferroptosis by Regulating the miR-142-3p/ACSL4 Molecular Axis

  • 期刊论文

  • 发表日期：

    2026年6月20日

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  • Yuejin Li,
  • Yiming Ouyang,
  • Yu Zhu,
  • Dezhi Hou,
  • Xing Li,
  • Xiaodong Guo,
  • Ping Sheng,
  • Hailong Wu,
  • Yingzhong Liao,
  • Kunmei Gong,
  • Linhai Li

摘要

Natural killer (NK) cells play a crucial role in combating gastric cancer (GC). However, they undergo ferroptosis in the tumor microenvironment of GC, which weakens their antitumor effects. Exosomal circRNA influences GC progression. Previous studies have reported the cancer-promoting role of circPDSS1 in GC, but whether it is involved in NK cell ferroptosis remains unclear. This study aimed to investigate the role of GC cell-derived exosomal circPDSS1 in NK cell ferroptosis. A noncontact coculture system of GC cells (HGC-27, AGS, and MKN-45 cells) and human NK-92 cells was established, and humanized mouse and cell-derived xenograft (CDX) tumor models were constructed for joint investigation. Cell death and viability were assessed via flow cytometry, LDH release assays and CCK-8 assays; circPDSS1 stability was determined by agarose gel electrophoresis and actinomycin D treatment; ferroptosis was determined by measuring lipid ROS, MDA, and Fe2+ levels; and key molecular interactions were determined by performing dual-luciferase reporter assays and RIP and RNA pull-down experiments. CD56 and CD16 expression was reduced in clinical tumor tissues. In vitro experiments revealed that the proportion of 7-AAD+ NK-92 cells cocultured with GC cells was significantly increased, accompanied by increased cell mortality and decreased IFN-γ and TNF-α secretion. Further studies revealed that circPDSS1 expression was abnormally elevated in GC tissues and cells and was particularly enriched in MKN-45 cell-derived exosomes (Exos). Knockdown of circPDSS1 alleviated MKN-45-Exo-induced cell damage; reduced lipid ROS, MDA, and Fe2+ levels in NK-92 cells; and delayed tumor progression. Furthermore, a ferroptosis inhibitor suppressed circPDSS1 overexpression-induced cell death. Mechanistically, circPDSS1 sponged miR-142-3p to upregulate ACSL4 expression, promoting NK cell ferroptosis. Exosomal circPDSS1 derived from GC cells contributes to NK cell ferroptosis by sponging miR-142-3p to increase ACSL4 expression and exacerbate GC.