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<p>Ovarian cancer remains a leading cause of gynecologic cancer mortality, largely due to high recurrence and frequent cisplatin resistance. This study investigates the role of ADAR1 lactylation-mediated RNA editing in ovarian cancer chemoresistance. Cisplatin-resistant cells exhibit significantly elevated global adenosine-to-inosine (A-to-I) RNA editing and ADAR1 expression. Genetic knockdown of ADAR1 enhances cisplatin sensitivity in vitro and in vivo, activates innate immune MAVS/PKR pathways, and promotes CD4⁺/CD8⁺ T cell infiltration. Mechanistically, Tip60 mediates ADAR1 lactylation, facilitating its interaction with deubiquitinase USP48 to stabilize ADAR1. Lactylation-dependent ADAR1 upregulation suppresses innate immunity and enhances protein translation, driving chemoresistance. Notably, inhibitor ZYS-1 targets ADAR1 lactylation, reducing ADAR1 expression, activating antitumor immunity, and synergizing with cisplatin to delay tumor growth in mice. These findings establish ADAR1 lactylation as a critical regulatory mechanism, supporting ZYS-1 plus cisplatin as a promising strategy for platinum-resistant ovarian cancer.</p>

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Targeting ADAR1 lactylation activates innate immune and overcomes chemoresistance in ovarian cancer

  • 期刊论文

  • 发表日期：

    2026年5月25日

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  • Linlu Cui,
  • Qihua Yi,
  • Chunyan Tang,
  • Qiuying Gu,
  • Qingya Luo,
  • Xin Luo,
  • Fatao Luo,
  • Li Li,
  • Tao Liu,
  • Ping Yi

摘要

Ovarian cancer remains a leading cause of gynecologic cancer mortality, largely due to high recurrence and frequent cisplatin resistance. This study investigates the role of ADAR1 lactylation-mediated RNA editing in ovarian cancer chemoresistance. Cisplatin-resistant cells exhibit significantly elevated global adenosine-to-inosine (A-to-I) RNA editing and ADAR1 expression. Genetic knockdown of ADAR1 enhances cisplatin sensitivity in vitro and in vivo, activates innate immune MAVS/PKR pathways, and promotes CD4⁺/CD8⁺ T cell infiltration. Mechanistically, Tip60 mediates ADAR1 lactylation, facilitating its interaction with deubiquitinase USP48 to stabilize ADAR1. Lactylation-dependent ADAR1 upregulation suppresses innate immunity and enhances protein translation, driving chemoresistance. Notably, inhibitor ZYS-1 targets ADAR1 lactylation, reducing ADAR1 expression, activating antitumor immunity, and synergizing with cisplatin to delay tumor growth in mice. These findings establish ADAR1 lactylation as a critical regulatory mechanism, supporting ZYS-1 plus cisplatin as a promising strategy for platinum-resistant ovarian cancer.