Neocryptomerin targets NAE1 to induce DNA re-replication and DNA damage by inhibiting neddylation-mediated CDT1 degradation in gastric cancer

Gastric Cancer (GC) remains a globally prevalent malignancy, necessitating the development of effective therapeutics. Natural products are an important source for the development of anti-tumor drugs. Neocryptomerin (Neo) is a natural biflavonoid derived from Selaginella Herba, yet its efficacy and mechanism against GC were unexplored. This study demonstrated that Neo significantly reduced the proliferation and triggered Apoptosis of GC cells. Neo induced DNA re-replication, S-phase arrest, and DNA damage in these cells. Additionally, Neo substantially suppressed tumor growth in a HGC-27 xenograft mouse model, achieving a 68.39% tumor inhibition rate. Moreover, Neo suppressed cell proliferation and promoted Apoptosis in tumor tissues from mice. Mechanistically, upregulation of CDT1 was involved in Neo-induced DNA re-replication, S-phase arrest, and DNA damage in GC cells. Importantly, Neo suppressed neddylation by targeting NAE1 in GC cells. Altering NAE1 expression notably decreased the sensitivity of GC cells to Neo treatment. Moreover, NAE1 was involved in Neo's regulation of neddylation and CDT1. In addition, NAE1 had oncogenic potential in GC. Collectively, Neo exhibited significant anti-GC activity through targeting NAE1 to induce DNA re-replication, S-phase arrest, and DNA damage by inhibiting neddylation-mediated CDT1 degradation. Therefore, as a novel natural neddylation pathway inhibitor, Neo is a promising candidate drug for GC treatment. NAE1 could serve as a potential therapeutic target for GC. This work offers a new strategy for the development of novel neddylation pathway inhibitors.