RBM17 promotes hepatocellular carcinoma progression by regulating lipid metabolism and immune microenvironment:...

Variable splicing (AS) plays important roles in tumor progression. However, the role of the AS factor RBM17 in the progression of hepatocellular carcinoma (HCC) has not yet been elucidated. We used label-free proteomics, single-cell sequencing (scRNA-seq), high throughput sequencing, flow cytometry (FCM), liquid Chromatography-tandem mass spectrometry (LC‒MS/MS), multiparametric immunofluorescence (mIF) and chromatin immunoprecipitation (Chip), to explore the relationship between RBM17 regulation of HCC cell lipid metabolism and the immune microenvironment. Our findings revealed that RBM17 is significantly overexpressed in HCC tissue and is positively correlated with poor prognosis. We found a positive correlation between RBM17 expression and M2 macrophage infiltration. Mechanistically, RBM17 promotes M2 macrophage infiltration by inducing taurocholic acid (T-CA) production, which is achieved through enhancing exon exclusion of CSAD precursor mRNA. Additionally, RBM17 modulates fatty acid metabolism and CD8⁺ T cell infiltration by regulating exon skipping in HACD3 precursor mRNA. Furthermore, RUNX1 activates RBM17 expression and regulates downstream CSAD/T-CA and HACD3/FFA signaling. Importantly, targeting RBM17 can prevent HCC progression, suggesting its potential as a therapeutic target for HCC. Our findings provide new insights into the mechanisms underlying immune cell infiltration and metabolism in HCC and identify RBM17 as a promising therapeutic target.