Abstract 195: IL-33/JAK2/RAB21/PLD4-Sphingolipid network drives gastric carcinogenesis.

Abstract Gastric cancer (GC), the fifth most prevalent malignancy and fourth leading cause of cancer mortality globally, is synergistically promoted by Helicobacter pylori infection and alcohol consumption through exacerbated gastric mucosal inflammation. To delineate key biomarkers in the gastritis-to-cancer transition and identify actionable targets for primary prevention and therapy, we integrated proteomic and metabolomic analyses of Helicobacter pylori plus alcohol induced GC mouse model and human gastritis/GC tissues. It revealed that significant Ras-related protein RAB21 is upregulated in gastritis and gastric cancer tissues, and metabolomics identified sphingolipid metabolism reprogramming is a key signature in GC tumorigenesis. In vitro experiments showed that RAB21 downregulation suppressed GC cell proliferation, and in vivo studies including RAB21 conditional knockout mice further demonstrated that RAB21 depletion inhibited GC tumorigenesis. Mechanistically, RAB21 binds to tyrosine-protein kinase JAK2 and is phosphorylated at tyrosine 88 by JAK2, regulating expression and phospholipase activity of 5'-3' exonuclease PLD4. Helicobacter pylori plus alcohol induced upregulated interleukin-33 (IL-33) promotes JAK2 and RAB21 expression via forkhead box protein P3 (FOXP3), promoting RAB21 nuclear translocation to regulate PLD4 expression, and converged with the phosphatidic acid-sphingosine kinase-sphingosine-sphingosine 1-phosphate (PA-SPHK-SPHG-S1P) metabolic flux to drive GC tumorigenesis and progression. This study elucidates the protein-metabolic network in gastric carcinogenesis and provides experimental rationale for targeting IL-33/JAK2/RAB21/PLD4-sphingolipid metabolism axis for GC prevention and treatment. Citation Format: Hui Liu, Yunxiao Ge, Yubing Zhou, Hangrui Liu, Zigang Dong. IL-33/JAK2/RAB21/PLD4-Sphingolipid network drives gastric carcinogenesis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 195.