The resveratrol-induced apoptosis and/or necroptosis of lung cancer cells is dependent on the activation status of PARP-1 and MLKL under oxidative stress.

[UNLABELLED] While numerous studies have described the anticancer effects of resveratrol (RES), some aspects of its underlying molecular mechanisms remain to be elucidated. In this study, we investigated the molecular mechanisms by which RES attenuates lung cancer progression. RES inhibited cell growth by blocking G1/S and G2/M transitions in a concentration-dependent manner. It also concentration-dependently increased the number of cells with apoptotic nuclei. This effect was associated with caspase-9-dependent apoptosis and with necroptosis induced by phospho-receptor interacting protein 1 (P-RIP1) and phospho-mixed lineage kinase domain-like protein (P-MLKL) downstream of apoptosis. Furthermore, RES treatment induced poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation, which was enhanced by NAD⁺ supplementation, leading to increased apoptosis and necroptosis. Conversely, PARP-1 inhibition decreased P-RIP1 and P-MLKL levels, thereby suppressing necroptosis while simultaneously increasing apoptosis. Therefore, the PARP-1 and MLKL activation status plays a crucial role in RES-induced cell death. RES induced the degradation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidants, including heme oxygenase-1 (HO-1) and disrupted the mitochondrial membrane potential. Hemin-induced HO-1 upregulation counteracted RES-induced Nrf2 degradation and increased PARP-1 activation-mediated necroptosis. Compared with RES, -acetylcysteine (NAC) slightly reduced RES-induced Nrf2 and HO-1, but upregulated catalase and SOD2 and increased PARP-1 cleavage and P-γH2AX level. RES or NAC treatment alone reduced hemin-induced reactive oxygen species (ROS) levels but generated ROS when combined. This suggests that RES scavenges ROS, and their excessive removal by NAC may paradoxically generate more of them. In conclusion, RES exerts anticancer effects through cell cycle arrest, mitochondria-mediated apoptosis, and PARP-1 hyperactivation-mediated necroptosis.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s43188-026-00351-1.