TPL2 Promotes Gastric Cancer Progression and Chemoresistance Through a Hypoxia-Induced Positive Feedback Loop with PPARδ

Tumor progression locus 2 (TPL2), a member of the MAP3K serine/threonine protein kinase family, is implicated in immune responses and pro-inflammatory protein phosphorylation. Emerging evidence suggests its role in tumorigenesis; however, its contribution to gastric cancer (GC) development remains unclear. Patients' disease progression and tumor tissues obtained were used to perform gene expression and GSEA analysis. Immunohistochemical staining, <i>EMSA</i>, ChIP, immunoprecipitation analyses, confocal microscope image and molecular docking were conducted to investigate the relationship between TPL2 and Peroxisome proliferator-activated receptor delta (PPARδ). Xenograft mouse models were used to study the role of PPARδ/TPL2 axis in tumor growth and the efficacy of blocked TPL2. TPL2 expression was significantly upregulated in GC tissues compared to adjacent normal tissues, and high TPL2 levels correlated with poor patient outcomes. Silencing TPL2 via siRNA or pharmacological inhibition suppressed GC cell proliferation and enhanced sensitivity to doxorubicin (Adriamycin), whereas TPL2 overexpression promoted tumor growth and chemoresistance. Mechanistically, TPL2 activated hypoxia/PPARδ signaling by interacting with PPARδ, thereby enhancing its transcriptional activity. Furthermore, PPARδ transcriptionally upregulated TPL2 expression, establishing a positive feedback loop. Functional studies confirmed the interdependent relationship between TPL2 and PPARδ in regulating GC cell proliferation and drug resistance. This study identifies a novel TPL2/PPARδ positive feedback regulatory loop that drives GC progression and chemoresistance. Targeting this axis may provide new therapeutic strategies not only for GC but also for other diseases associated with pathological hypoxia.