SRSF1/Mcl‐1 Axis Drives Apoptosis Evasion and Shapes the Immune Microenvironment to Promote Gastric Cancer Progression

Gastric cancer (GC) is one of the malignancies with the highest incidence and mortality worldwide. Evasion of apoptosis is a hallmark of cancer that drives tumor progression. The splicing factor SRSF1 and antiapoptotic protein Mcl‐1, including its isoforms Mcl‐1L and Mcl‐1S, play significant roles in cancer development; however, the regulatory mechanisms of the SRSF1‐Mcl‐1 axis in GC remain unclear. This study systematically evaluated the function of SRSF1 in GC by integrating multidatabase analyses (TIMER, UALCAN, and KM‐Plotter), in vitro experiments (qRT‐PCR, Western blot, Transwell migration/invasion, and apoptosis assays), in vivo xenograft models, and bioinformatic approaches (single‐cell RNA sequencing, hdWGCNA, cell interaction analysis, and mutational analysis). SRSF1 is significantly overexpressed in GC tissues and cell lines, correlating with poor prognosis in patients. Through comprehensive multiomics analysis, we first revealed that SRSF1‐positive malignant epithelial cells possess a unique coexpression network and exhibit significantly enhanced interactions with fibroblasts, reshaping the tumor microenvironment (TME). Subsequently, functional assays demonstrated that SRSF1 overexpression enhances cell invasion, migration, and apoptosis resistance by inhibiting the proapoptotic isoform Mcl‐1S and suppressing the mitochondrial apoptosis pathway (Bak/caspase‐9/caspase‐3). In conclusion, the SRSF1‐Mcl‐1 axis serves as a dual key regulator of invasion/migration and apoptosis evasion in GC, providing a new strategy for targeted therapy in advanced GC.