Ailanthone targets the EGR3-SOCS2 regulatory pathway to suppress vasculogenic mimicry in prostate cancer.

Prostate cancer (PCa) frequently progresses to castration-resistant stages with poor prognosis, in which vasculogenic mimicry (VM) contributes to tumor aggressiveness and therapeutic resistance. Here, we investigated the antitumor effects of the natural quassinoid Ailanthone (AIL) and its impact on VM in PCa. Our study demonstrates that AIL markedly suppresses PCa cell viability, induces apoptosis and G1/S cell-cycle arrest, and inhibits migration, invasion, stemness, and VM formation. Mechanistically, AIL enhances early growth response protein 3 (EGR3) binding to the promoter of suppressor of cytokine signaling 2 (SOCS2), leading to SOCS2 upregulation and subsequent inhibition of JAK/STAT3 signaling. Functional rescue experiments reveal that SOCS2 or EGR3 silencing partially reverses the inhibitory effects of AIL on malignant phenotypes and VM. In vivo, AIL significantly reduces tumor growth, promotes apoptosis, and attenuates VM formation, effects that are weakened upon SOCS2 knockdown. Collectively, these findings indicate that AIL exerts potent anti-tumor and anti-VM activities in PCa by activating the EGR3-SOCS2 axis and suppressing JAK/STAT3 signaling, highlighting its potential as a promising therapeutic strategy for advanced and treatment-resistant PCa.