Immunohistochemical analyses unveiled that erinacine S treatment significantly upregulates the expression of TRAIL, TNFR1, and DR5 proteins while downregulating p-AKT, p-ERK, HIF1α, PCNA, and NFκB levels in the xenograft mouse model of chemoresistant human CRC cells. This evidence concerns the gene HIF1A and colorectal carcinoma.