Pristimerin drives ROS-dependent apoptosis in cutaneous T-cell lymphoma via inhibition of the AKT-SKP2 axis

Cutaneous T-cell lymphoma (CTCL) is a skin-predominant form of non-Hodgkin lymphoma for which improved therapeutic options are needed. Here, we investigated the anti-lymphoma effects of pristimerin (PS) and defined its underlying mechanism in H9 and HH CTCL cell lines. PS strongly reduced cell growth and induced apoptosis, with hallmarks of mitochondrial (intrinsic) pathway activation, including caspase processing. PS also decreased basal AKT activity and downregulated pro-survival factors such as XIAP. In addition, PS reduced the abundance of S-phase kinase-associated protein 2 (SKP2) and was accompanied by increased levels of the cyclin-dependent kinase inhibitors p21^Cip1 and p27^Kip1. Genetic suppression of AKT intensified apoptosis-associated signaling, reflected by increased H2AX activation and PARP cleavage. Notably, PS elevated intracellular reactive oxygen species (ROS), and scavenging ROS with N-acetylcysteine (NAC) significantly attenuated PS-driven cytotoxicity, supporting a ROS-dependent mechanism. Finally, PS combined with the proteasome inhibitor bortezomib produced greater anti-CTCL activity than either agent alone, consistent with a synergistic interaction. Together, these findings show that PS promotes ROS-dependent, mitochondria-mediated apoptosis in CTCL and support further evaluation of PS-based strategies for this malignancy.