The present study shows that α‐hed induced paraptosis‐like cell death, the proparaptotic activity of α‐hed in CRC cells was mediated through targeting G‐protein‐coupled receptors (GPCRs) to activate phospholipase C (PLC)‐β3, PLCβ3 produced signals to stimulate calcium (Ca2+) signaling by activation of inositol 1,4,5‐trisphosphate receptor (IP3R), which subsequently activated protein kinase C alpha (PKCα) and led to the MAPK activation. The gene discussed is PLCB3; the disease is colorectal carcinoma.