Helicobacter pylori activates the TRAF1/OASL/ZBP1-PANoptosome pathway to induce PANoptosis in the gastric mucosa

Abstract

Helicobacter pylori (H. pylori) has been identified as a pathogenic factor in gastric cancer (GC). Building on our previous findings that VacA upregulates TRAF1, which in turn transcriptionally activates OASL, we explored the role of this TRAF1-OASL-PANoptosis axis in GC using clinical samples, cell lines, and mouse models. Functional assays (CCK-8, colony formation, migration, invasion, TUNEL) demonstrated that TRAF1 promotes GC cell proliferation, migration, and invasion via OASL, while suppressing apoptosis. RNA-seq revealed that upregulation of TRAF1 and OASL, combined with H. pylori infection in gastric epithelial cells, enriched pathways associated with PANoptosis. Rescue experiments showed that TRAF1 knockdown increased PANoptosis, and this increase was attenuated by the pan-caspase inhibitor Z-VAD-FMK, whereas subsequent OASL overexpression reversed the suppression of PANoptosis caused by TRAF1 knockdown, whereas LPS further induced PANoptosis. Both in vitro and in vivo models confirmed that H. pylori infection triggers PANoptosis. Co-Immunoprecipitation assays uncovered a protein interaction between OASL and the ZBP1-PANoptosome. Critically, under H. pylori infection conditions, OASL overexpression rescued the PANoptosis suppressed by TRAF1 knockdown in gastric epithelial cells. This study demonstrates that H. pylori infection induces PANoptosis, and defines a pathway wherein TRAF1 promotes PANoptosis by regulating OASL-mediated activation of the ZBP1-PANoptosome. Our findings reveal a novel, context-dependent duality of the TRAF1/OASL axis: it promotes PANoptosis, contributing to mucosal damage during the precancerous inflammatory stage, yet in established GC, this axis appears to suppress PANoptosis, facilitating tumor progression. These insights provide a theoretical foundation for targeting this pathway in treating H. pylori-associated gastritis-cancer progression.

Keywords: Helicobacter pylori; Gastric cancer; OASL; PANoptosis; TRAF1; ZBP1-PANoptosome.