Constitutive NF-kappa B activation is required for survival of activated B cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL). However, current NF-kappa B targeting strategies lack cancer cell specificity. Here, we identified a novel inhibitor, piperlongumine, features direct binding to NF-kappa B p65 subunit and suppression of p65 nuclear import. This was accompanied by NF-kappa B reporter activity suppression and NF-kappa B target gene downregulation. Moreover, mutation of Cys(38) to Ser in p65 abolished this effect of piperlongumine on inhibition of p65 nuclear import. Furthermore, we show that piperlongumine selectively inhibited proliferation and induced apoptosis of ABC-DLBCL cells. Most notably, it has been reported that piperlongumine did not affect normal cells even at high doses and was nontoxic to animals. Hence, our current study provides new insight into piperlongumine's mechanism of action and novel approach to ABC-DLBCL target therapy. (C) 2015 Elsevier Inc. All rights reserved.