The inhibitor of SHMT synergizes with 5-Fu repression gastric cancer through promoting cell cycle arrest and alleviating chemoresistance
Advanced gastric cancer (GC) requiring an in-depth investigation into its mechanisms of progression and the development of effective therapeutic strategies. Serine hydroxymethyltransferase (SHMT), an essential enzyme in the serine-glycine-nucleotide metabolic network, is crucial for the initiation and advancement of GC. In this study, bioinformatics analyses and cytological experiments were employed to preliminarily establish the critical role of SHMTs in GC progression. Drug synergy screening assays were conducted to construct a therapeutic model, while transcriptomic analyses elucidated the underlying mechanisms of combination therapy. Our findings demonstrated that SHMT1 and SHMT2 drive malignant progression and confer resistance to 5-fluorouracil (5-Fu) in GC. SHIN1, a targeted SHMT inhibitor, emerged as a promising antitumor agent for GC. Synergistic screening revealed that SHIN1 acts as an efficient synergist for 5-Fu, with the combination therapy significantly alleviating 5-Fu resistance in GC. Mechanistically, the combination treatment induced cell cycle arrest, DNA damage, and cellular senescence by regulating the P53 signaling pathway. These unique growth-inhibitory effects, achieved through interference with nucleotide synthesis, were validated in extensive assays. In conclusion, the combination of SHIN1 with 5-Fu represents a promising preclinical model for GC treatment, offering a novel strategy to overcome drug resistance and improve therapeutic efficacy.