The herbal compound miltirone from Salvia miltiorrhiza targets DJ-1 to induce mitophagic dysfunction and ROS-dependent hippo activation in gastric cancer

A total of 596 compounds were identified from SME, among which Miltirone directly bound to the DJ-1 protein (KD = 3.89 μM) and inhibited its antioxidant function. Miltirone significantly suppressed gastric cancer cell proliferation and induced apoptosis both in vitro and in vivo, while also causing mitochondrial dysfunction, autophagy impairment, and ROS accumulation. Furthermore, Miltirone activated the CBP/MOB1 axis in a ROS-dependent manner, promoting MOB1 phosphorylation and subsequently activating the Hippo pathway, leading to YAP phosphorylation and degradation. Inhibition of the Hippo pathway reversed the anti-tumor effects of Miltirone, indicating that activation of the Hippo signaling pathway is responsible for Miltirone-mediated anti-gastric cancer activity.