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<p>Ferroptosis has emerged as a potential therapeutic target in cancer. This study shows the critical role of AGR2 in ferroptosis suppression across pancreatic cancer cell lines and in vivo models. Notably, human pancreatic cancer cells exhibit dose-dependent AGR2 upregulation upon exposure to ferroptosis inducers. Genetic ablation of AGR2 significantly sensitizes cells to ferroptosis through a p53-mediated mechanism, while p53 knockdown effectively rescues ferroptosis resistance. Mechanistic investigations demonstrate that AGR2 deficiency activates p53 signaling, downregulating the iron exporter SLC40A1 (encoding ferroportin/FPN1), inducing intracellular iron overload and consequent ferroptosis. Clinically, we find a positive correlation between AGR2 and FPN1 expression in PDAC specimens, with co-elevation of both markers predicting unfavorable patient prognosis. Therapeutically, administration of an AGR2-targeting peptide synergizes with ferroptosis inducers, significantly enhancing cell death in PDAC models. Our findings not only elucidate a novel AGR2/p53/FPN1 regulatory axis in ferroptosis control but also propose innovative combination strategies for pancreatic cancer treatment.</p><p></p>

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AGR2 suppresses ferroptosis via the p53/FPN1 regulatory axis and drives therapeutic vulnerabilities in pancreatic cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月1日

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  • Ziying Jian,
  • Jialin Song,
  • Liangqi Lu,
  • Tao Pan,
  • Hanzhe Zhang,
  • Qi Zhang,
  • Weiyu Zhang,
  • Renjie Li,
  • Jizhou Gong,
  • Naipeng Shi,
  • Shi Zuo,
  • Tao Cheng,
  • Yuhong Yang,
  • Zhiheng Zhang

摘要

Ferroptosis has emerged as a potential therapeutic target in cancer. This study shows the critical role of AGR2 in ferroptosis suppression across pancreatic cancer cell lines and in vivo models. Notably, human pancreatic cancer cells exhibit dose-dependent AGR2 upregulation upon exposure to ferroptosis inducers. Genetic ablation of AGR2 significantly sensitizes cells to ferroptosis through a p53-mediated mechanism, while p53 knockdown effectively rescues ferroptosis resistance. Mechanistic investigations demonstrate that AGR2 deficiency activates p53 signaling, downregulating the iron exporter SLC40A1 (encoding ferroportin/FPN1), inducing intracellular iron overload and consequent ferroptosis. Clinically, we find a positive correlation between AGR2 and FPN1 expression in PDAC specimens, with co-elevation of both markers predicting unfavorable patient prognosis. Therapeutically, administration of an AGR2-targeting peptide synergizes with ferroptosis inducers, significantly enhancing cell death in PDAC models. Our findings not only elucidate a novel AGR2/p53/FPN1 regulatory axis in ferroptosis control but also propose innovative combination strategies for pancreatic cancer treatment.