Colorectal cancer (CRC) is the second leading cause of malignant-associated death in the USA with inflammation as a key driving force for its development, growth, and progression. p38, a member of p38 mitogen-activated protein kinases (p38 MAPK , and ), is oncogenic, pro-inflammatory, and overexpressed in clinical CRC but the role of epithelial p38 in CRC tumorigenesis has not been tested. - catenin, a critical cofactor of Wnt transcription, is aberrantly activated in 90% of CRC. And yet, -catenin is undruggable and there is thus an urgent need to identify druggable -catenin activators for therapeutic intervention. Here we propose that p38 MAPK in intestinal epithelial cells (IEC) drives CRC tumorigenesis by stimulating oncogenic -catenin phosphorylation. This hypothesis is based on our preliminary studies showing that: 1) inflammation coordinately stimulates p38 and -catenin phosphorylation in CRC cells; 2) p38 directly phosphorylates -catenin at S605, which increases -catenin stability, the -catenin-TCF4 interaction, Wnt transcription and CRC growth; 3) inflammation activates p38, but not p38, in intestinal tissues of mice, and IEC-specific p38 knockout (KO) reduces pro-inflammatory cytokine expression and attenuates colitis severity; 4) IEC p38 KO inhibits colon tumorigenesis and p--catenin/S605/Wnt signaling in the azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model of colitis-associated cancer (CAC); 5) the p38 pharmacological inhibitor pirfenidone (PFD) suppresses -catenin/cytokine expression and colon tumorigenesis in wild-type (WT) mice, but not in p38 KO mice, and further collaborates with the -catenin-TCF4 interaction antagonist LF3 and chemotherapeutic drug 5FU to inhibit CRC growth, and 6) p38 is upregulated in clinical CAC specimens and in intestinal tissues of Apcmin and interleukin-10 knockout (IL-10-/-) mice. These results together indicate that IEC p38 is required for tumorigenesis of both CAC and sporadic CRC by stimulating oncogenic -catenin phosphorylation. Using genetic and pharmacological approaches, we will test this hypothesis by determining (1) if p38- induced -catenin/S605 phosphorylation stimulates -catenin nuclear translocation, -catenin-TCF4 interaction, Wnt transcription and CRC growth; (2) if IEC-specific p38 KO blocks tumorigenesis in IL- 10-/- and Apcmin mice and if p38 is essential for the -catenin/TCF4/Wnt signaling to promote malignant progression in CRC pathogenesis; and (3) if the p38 pharmacological inhibitor pirfenidone (PFD) blocks CRC tumorigenesis and increases the growth-inhibitory activity of LF3 and 5FU by disrupting the p38/-catenin/TCF4/Wnt pathway. Upon completion, these studies will demonstrate if epithelial p38 promotes CRC tumorigenesis by stimulating oncogenic -catenin/S605 phosphorylation and Wnt transcription. Demonstrating the effectiveness of PFD in inhibiting Wnt signaling and CRC tumorigenesis by targeting intestinal epithelial p38 wil...