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

  • Cell Death Differ. 2026 May 25. doi: 10.1038/s41418-026-01760-3.
Linlu Cui  #  1 ,  Qihua Yi  #  1  2 ,  Chunyan Tang  #  1  3 ,  Qiuying Gu  1 ,  Qingya Luo  4 ,  Xin Luo  1 ,  Fatao Luo  1 ,  Li Li  5 ,  Tao Liu  6 ,  Ping Yi  7
Affiliations
  • 1. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2. Department of Gynecology, Chongqing University Three Gorges Hospital, Chongqing University Medical School, Chongqing, China.
  • 3. Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 4. Department of Pathology, Southwest Hospital, Army Medical University, Chongqing, China.
  • 5. Department of Obstetrics and Gynecology, Army Specialty Medical Center, Army Medical University, Chongqing, China.
  • 6. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • 7. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. [email protected].
  • # Contributed equally.
PMID: 42185630 DOI: 10.1038/s41418-026-01760-3
Abstract

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.

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