SKQ1 promotes tumor cell apoptosis by directly interacting with NDUFV2 and inducing superoxide production.

SKQ1, a mitochondria-targeted antioxidant composed of triphenylphosphonium (TPP+) and plastoquinone, has been reported to exhibit antitumor potential; however, its underlying mechanism of action and specific molecular targets remain largely unclear. Here, we investigated the antitumor efficacy of SKQ1 in vitro using human hepatocellular carcinoma cells (MHCC97-H) and murine colorectal cancer cells (MC38), and in vivo using a human-derived hepatocellular carcinoma xenograft model and a murine syngeneic colorectal cancer model. We found that SKQ1 induced apoptosis and inhibited the proliferation and migration of both MHCC97-H and MC38 in vitro; correspondingly, it also suppressed tumor development in a human-derived hepatocellular carcinoma xenograft model and a murine syngeneic colorectal cancer model established with these cells in vivo. It increased intracellular ROS levels. Mitochondria-targeted antioxidant Mito-TEMPO could rescue the pro-apoptotic effect of SKO1. Furthermore, NDUFV2 was identified as the direct target of SKQ1. SKQ1 binding to NDUFV2 induced the dysfunction of mitochondrial complex I, leading to a burst of ROS. NDUFV2 knockout eliminated the effect of SKQ1. Our findings demonstrated that SKQ1 exerts its antitumor effects by directly targeting NDUFV2, thereby inducing mitochondrial dysfunction and ROS-mediated apoptosis, which provides a mechanistic basis for developing SKQ1 as a potential anticancer therapeutic agent.