Targeting YBX1: A novel therapeutic strategy for gastric cancer through regulation of cellular senescence and mTOR signaling.

Gastric cancer (GC) continues to pose a significant challenge for treatment due to its heterogeneity and the limitations of current strategies. There is an urgent need to find new molecular targets and strategies that can overcome therapy limitations and enhance outcomes. The modern "one-two punch" therapy involves inducing senescence and using a second drug to target senescent cancer cells, potentially offering an effective treatment. However, it remains an emerging research area for GC. In this study, we aimed to investigate the role of YBX1, a multifunctional RNA- and DNA-binding protein, in GC progression and its therapeutic potential in senescence-based strategies. We found that YBX1, which is elevated in gastric cancer cells and correlated with poor prognosis in gastric cancer patients, acts as a central hub linking the mTOR, ROS, and DDR pathways. YBX1 mRNA and protein levels were significantly higher in GC tissues than in adjacent normal tissues (P < 0.001), and high expression was associated with reduced overall survival (P < 0.05). Importantly, YBX1 promotes the proliferation of GC cells (P < 0.01) and inhibits senescence by regulating the mTOR signaling pathway. Targeting YBX1 could offer a "one-two punch" therapeutic approach for GC, since inhibiting mTOR induces senolytic effects on senescent cancer cells. Furthermore, YBX1 knockdown increases ROS levels (P < 0.0001) and disrupts DNA damage repair, enhancing its potential as a therapeutic target. In vivo xenograft studies confirmed that YBX1 inhibition reduces tumor growth and downregulates Ki67, pmTOR, and p4EBP1 expression (P < 0.001), while upregulating cellular senescence markers (P < 0.01), supporting its critical role in GC progression. Thus, this study underscores YBX1 as a pivotal regulator of GC cell proliferation, senescence, and survival, offering a promising avenue for targeted therapies. By leveraging YBX1 inhibition, this work lays a foundation for developing precision medicine approaches in GC treatment.