Fig. 1

Main signaling pathways involved in TPL in cancer. (A)TPL dampens the activation of the STAT3 signaling pathway by preventing STAT3 from binding to DNA. Simultaneously, it disrupts the binding interaction between Beclin1 and Mcl-1, resulting in decreased expression of genes controlled by STAT3, which are associated with anti-apoptotic, proliferative, and angiogenic functions. (B)TPL effectively inhibits NF-κB activity and reduces the protein expression of its subunits, c-Rel and Rel-A. Simultaneously, TPL binds to and activates p38α and ERK1/2, stabilizes p53, and inhibits IκBα phosphorylation. (C)TPL hinders the Wnt/β-catenin signaling pathway through the suppression of LRP6 phosphorylation, subsequently inhibiting DSH activation. This action leads to heightened expression of CDH1, WIF1, and other related factors. Additionally, TPL induces demethylation to provide further inhibition of the Wnt signaling pathway. (D)TPL enhances TRAIL-related signaling activation by increasing DR5 expression and reducing PUM1 expression, rendering cells more sensitive to apoptosis. It leads to an increase in p27 and CDK2 complexes, inducing autophagy. When combined with TRAIL, TPL causes lysosome-dependent cell death