Dillon M. Voss, Yange Cui, Peter S. Klein
Aberrant RNA splicing and metabolic reprogramming are defining hallmarks of cancer that were historically studied as parallel processes. Increasing evidence now reveals extensive crosstalk between these pathways, whereby RNA splicing reshapes metabolic circuits, and metabolic states reciprocally influence splice-site selection and spliceosome activity. In this review, we synthesize recent mechanistic insights into how splicing programs regulate metabolic adaptation across diverse cancer contexts. We discuss recurrent oncogenic mutations in spliceosomal components and dysregulation of RNA-binding proteins (RBPs) that drive alternative splicing events in key metabolic regulators, which promote metabolic plasticity required for tumor growth. We further examine how metabolites and nutrient-sensing pathways directly modulate splicing factor activity, spliceosome dynamics, and RNA processing. We also summarize a new mechanism of mitochondrial quality control mediated by retrograde signals from mitochondria to the spliceosome to enhance mitophagy of dysfunctional mitochondria.