Halofuginone suppresses gastric tumor growth by inducing ROS-dependent inhibition of the PI3K/AKT pathway

Despite advances in diagnosis and therapy, the survival rate for gastric cancer, particularly in advanced stages, remains exceedingly low. Current chemotherapy regimens frequently lead to treatment failure and recurrence due to severe drug resistance and toxicity, underscoring the urgent need for novel therapeutic strategies with new mechanisms of action capable of effectively overcoming resistance. Natural products and their derivatives have attracted significant attention as a rich source of anticancer agents. Halofuginone (HF), a plant-derived natural compound possessing multi-target antitumor properties, has emerged as a highly promising anticancer candidate. However, its antitumor efficacy against gastric cancer and the precise underlying molecular mechanisms remain largely unexplored. This study aimed to investigate the effects and mechanisms of HF in SGC7901 and MKN45 cell lines. Our experiments demonstrated that HF inhibited gastric cancer cell proliferation while inducing apoptosis and S-phase cell cycle arrest. Mechanistically, HF triggered excessive mitochondrial reactive oxygen species (ROS) production, subsequentlysuppressing the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pro-survival pathway. Scavenging ROS with N-acetylcysteine (NAC) reversed these effects, confirming ROS as the central mediator of HF's antitumor activity. In a mouse xenograft model, HF administration inhibited primary tumor growth without inducing hepatorenal toxicity. These findings reveal a ROS-centric mechanism through which HF suppresses gastric cancer progression, positioning it as a promising therapeutic candidate to address unmet clinical needs in gastric cancer management.