Exploring the Anticancer Potential of Pterostilbene Through Modulation of the NRF2‐NFκB‐COX‐2 Network

Pterostilbene (PTS) is a naturally occurring analogue of resveratrol (RES) with high bioavailability, making it a promising alternative for diverse biological applications. PTS exhibits dose-dependent effects on cellular signaling, which require careful evaluation for therapeutic use. In this study, we used reporter gene-based bioassays and immunoblot analyses to examine the effects of PTS on Nrf2, COX-2, NF-κB, and GSK-3β signaling. Our results demonstrated that lower doses of PTS (2.5-5 µM) activate protective signaling pathways, including Nrf2 and COX-2, promoting adaptive and cytoprotective responses. In contrast, higher doses (10-25 µM) suppress pro-survival pathways, including NF-κB and COX-2, leading to potential cytotoxic effects. Specifically, PTS activated Nrf2 in a dose-dependent manner, enhancing downstream targets such as HO-1 and SOD2 involved in oxidative stress response. COX-2 was upregulated at 2.5-5 µM but suppressed at 25 µM. Similarly, NF-κB signaling was activated at lower doses but inhibited at higher concentrations, as confirmed by reduced nuclear translocation of the p65 subunit. Interestingly, PTS did not interfere with COX-2 inhibition when cells were treated with the non-selective inhibitor Indomethacin. These findings suggest that PTS influences stress response and survival pathways in a context-dependent manner. However, mechanistic crosstalk between NrfF2, NF-κB, COX-2, and GSK-3β remains to be established.