MAP3K13-232aa encoded by circMAP3K13 enhances cisplatin-induced pyroptosis by directly binding to IKKα in gastric adenocarcinoma

Cell Death Dis. 2025 Sep 1;16(1):667. doi: 10.1038/s41419-025-07991-5.

Abstract

Gastric cancer (GC) is one of the most common and lethal malignancies in developing countries, with particularly high prevalence in China. Circular RNAs (circRNAs) have garnered increasing attention for their roles in disease pathogenesis. While circRNAs can be translated, there have been few investigations into the biological functions of "translatable circRNAs" in the initiation and progression of gastric adenocarcinoma. In this study, we identified a circRNA, circMAP3K13, which inhibits the proliferation and migration of GC cells. CircMAP3K13 was found to encode a previously unreported 26 kDa protein, designated MAP3K13-232aa. Mechanistically, MAP3K13-232aa binds directly to the kinase domain of IKKα and enhances its activity, thereby promoting NF-κB signaling. This activation leads to upregulation of NLRP3 and increased cisplatin-induced pyroptosis in GC cells. Moreover, MAP3K13-232aa enhances pyroptosis and reduces tumorigenicity and metastasis in vivo. Taken together, both circMAP3K13 and its encoded protein MAP3K13-232aa represent potential therapeutic targets in GC.

MeSH terms

  • Adenocarcinoma* / drug therapy
  • Adenocarcinoma* / genetics
  • Adenocarcinoma* / metabolism
  • Adenocarcinoma* / pathology
  • Animals
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cisplatin* / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • I-kappa B Kinase* / genetics
  • I-kappa B Kinase* / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • NF-kappa B / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Protein Binding
  • Pyroptosis* / drug effects
  • Pyroptosis* / genetics
  • RNA, Circular* / genetics
  • RNA, Circular* / metabolism
  • Signal Transduction / drug effects
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / metabolism
  • Stomach Neoplasms* / pathology

Substances

  • Cisplatin
  • RNA, Circular
  • I-kappa B Kinase
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • CHUK protein, human
  • NF-kappa B