Double strike on TRKC: The nobiletin-SAHA alliance

Targeting apoptosis and autophagy has emerged as one of the most promising therapeutic avenues in NSCLC, however, current BH3 mimetics exhibit a narrow anti-tumor spectrum and serious adverse effects, and the synergistic therapeutic mechanism with epigenetic modulators in solid tumors has not yet been fully explored.

Here, we propose a combination regimen of nobiletin with the HDAC inhibitor SAHA, and we demonstrate the synergistic inhibition of NSCLC growth in vitro and in vivo by regulating BH3-only protein expression and suppressing the NTRK3-mediated PI3K/AKT/mTOR pathway. Nobiletin, acting as a natural BH3 mimetic, facilitates the dissociation of the Beclin-1/BCL-2 complex to induce autophagy and apoptosis; while SAHA enhances histone acetylation to up-regulate BH3-only proteins, and the combination synergistically down-regulates TRKC expression and inhibits tumor cell migration.

This work provides a new strategy based on combining a natural BH3 mimetic with epigenetic modulators to enhance anti-tumor efficacy and reveals the critical role of TRKC in NSCLC. The work entitled “Nobiletin inhibits non-small cell lung cancer through TRKC and exhibits a synergistic effect with the HDAC inhibitor” was published on Chinese Journal of Natural Medicines (published on May 20, 2026).