10,11-Dehydrocurvularin suppresses non-small cell lung cancer by targeting PAICS and inducing apoptosis

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide, highlighting the urgent need for effective therapeutic agents. Natural products represent an important source of novel anticancer compounds. In this study, we investigated the anti-NSCLC activity of 10,11-dehydrocurvularin (DCV), a fungal-derived macrolide. DCV potently inhibited the proliferation of NSCLC cell lines (A549 and NCI-H1703) in a dose-dependent manner, with IC₅₀ values of 7.92 μM and 5.33 μM, respectively. Furthermore, DCV (30 mg/kg) markedly suppressed tumor growth in A549 xenograft models without causing evident systemic toxicity, as evidenced by reduced tumor volume and weight, with no significant changes in body weight or organ histopathology. Through RNA-seq, drug affinity responsive target stability, and molecular docking analyses, we identified phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), a key enzyme in de novo purine biosynthesis, as a direct binding target of DCV. Mechanistically, DCV engagement promoted PAICS protein downregulation and disrupted nucleotide metabolism, leading sequentially to mitochondrial dysfunction, reactive oxygen species accumulation, DNA damage, and cell cycle arrest, ultimately triggering intrinsic apoptosis. Collectively, these findings uncover the anti-NSCLC efficacy and mechanism of DCV, positioning it as a promising natural bioactive lead for subsequent pharmacological development against lung cancer.