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<p>Celecoxib, a selective COX-2 inhibitor, has demonstrated anti-liver cancer effects in various preclinical models and clinical traits. However, prolonged use of celecoxib can lead to drug resistance, necessitating higher doses to maintain efficacy, which often results in severe side effects, limiting its clinical application. This study aimed to identify strategies to overcome celecoxib resistance in liver cancer. CRISPR/Cas9 screening revealed that liver cancer cells compensated for celecoxib treatment by upregulating ALOX and CYP enzymes, facilitating AA metabolism to produce alternative downstream products. STAT6 was identified as a key regulator of ALOX15, ALOX12, and CYP2E1, acting as a resister to celecoxib. Celecoxib stimulation leaded to increased phosphorylation of STAT6, enhanced binding to the promoters of target genes such as ALOX15, and upregulation of downstream gene expression. Knockdown of STAT6 significantly enhanced celecoxib sensitivity in vitro and in vivo by blocking AA shunting mediated by these enzymes. Furthermore, AS1517499, a STAT6 inhibitor, showed strong synergy with celecoxib in liver cancer cells by inhibiting AA shunting. In conclusion, targeting STAT6 enhances the efficacy of celecoxib in liver cancer by suppressing AA shunting. The combination of AS1517499 and celecoxib holds promise as a novel therapeutic strategy for liver cancer.</p>

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Whole-gene CRISPR/cas9 library screen revealed targeting STAT6 increased the sensitivity of liver cancer to celecoxib via inhibiting arachidonic acid shunting

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月28日

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  • Chujiao Hu,
  • Zhirui Zeng,
  • Xin Bao,
  • Dahuan Li,
  • Huading Tai,
  • Haohao Zeng,
  • Cheng Luo,
  • Lei Tang,
  • Tengxiang Chen,
  • Shi Zuo

摘要

Celecoxib, a selective COX-2 inhibitor, has demonstrated anti-liver cancer effects in various preclinical models and clinical traits. However, prolonged use of celecoxib can lead to drug resistance, necessitating higher doses to maintain efficacy, which often results in severe side effects, limiting its clinical application. This study aimed to identify strategies to overcome celecoxib resistance in liver cancer. CRISPR/Cas9 screening revealed that liver cancer cells compensated for celecoxib treatment by upregulating ALOX and CYP enzymes, facilitating AA metabolism to produce alternative downstream products. STAT6 was identified as a key regulator of ALOX15, ALOX12, and CYP2E1, acting as a resister to celecoxib. Celecoxib stimulation leaded to increased phosphorylation of STAT6, enhanced binding to the promoters of target genes such as ALOX15, and upregulation of downstream gene expression. Knockdown of STAT6 significantly enhanced celecoxib sensitivity in vitro and in vivo by blocking AA shunting mediated by these enzymes. Furthermore, AS1517499, a STAT6 inhibitor, showed strong synergy with celecoxib in liver cancer cells by inhibiting AA shunting. In conclusion, targeting STAT6 enhances the efficacy of celecoxib in liver cancer by suppressing AA shunting. The combination of AS1517499 and celecoxib holds promise as a novel therapeutic strategy for liver cancer.