C-Phycocyanin （C-PC） is a type of widely recognized natural food colorant. It is also a kind of important functional food， possessing anti-inflammatory， antioxidant， and antineoplastic properties. Our previous study demonstrated that C-Phycocyanin could induce the apoptosis of non-small cell lung cancer（NSCLC） H1299 cells. In this study， we employed high-throughput transcriptome method to analyze the differential genes between phycocyanin treated and untreated H1299 cells， aiming at investigating the potential regulatory mechanism of phycocyanin in NSCLC cells. The results showed that phycocyanin could significantly suppress the expression of toll/interleukin-1 receptor domain-containing adapter protein （TIRAP） gene in H1299 cells. siRNA knockdown of TIRAP expression induced the abnormal changes of cellular morphology， cell proliferation ability decreasing， upregulation of Bax， and downregulation of Bcl-xL. Furthermore， siRNA knockdown TIRAP could also significantly inhibit the activity of NF-κB signaling in H1299 cells. The present study demonstrated that phycocyanin could induce the apoptosis of H1299 cells through downregulating TIRAP expression. This work have revealed the potential regulatory mechanism of phycocyanin in NSCLC cells， also provided the theoretical basis of lung cancer treatment and functional foods application.