Landscape of splicing factors in early-onset gastric cancer reveals SRSF1 as a key driver of oxaliplatin resistance.

The incidence of early-onset gastric cancer (EOGC) is increasing. While RNA alternative splicing critically regulates cancer progression, and abnormal changes in splicing factors (SFs) can affect alternative splicing regulation, their roles in EOGC remain unclear. Using multi-omics approaches, we explored the expression and regulatory patterns of 75 SFs in EOGC and further analyzed the differences associated with different regulatory patterns. We investigated the role of serine/arginine-rich splicing factor 1 (SRSF1) in regulating oxaliplatin (OXA) resistance and malignant phenotypes in EOGC. The results showed that the expression levels of most SFs in the EOGC samples were significantly upregulated, while the somatic mutation rate of SFs was low. Based on the expression of SFs, the EOGC population can be stably divided into three splicing regulatory patterns, which differ in immune function, tumor mutational burden, and the anticipated response to chemotherapy drugs. Overexpressing SRSF1 confers OXA resistance to EOGC cells, promotes colony formation, and inhibits apoptosis, and it could promote exon skipping in downstream genes, thereby altering tumor-related functions. This study reveals the expression landscape of SFs in EOGC and highlights the disparities in biological functions across various splicing regulatory patterns. SRSF1 could be a potential therapeutic target and biomarker for overcoming OXA resistance in EOGC.