Metabolic Control of the Spliceosome in Cancer: Mechanisms, Evidence, and Therapeutic Vulnerabilities
Year: 2026
Type: article
Abstract: Aberrant RNA splicing is increasingly recognized as a fundamental feature of cancer, yet the metabolic mechanisms that regulate spliceosome function remain incompletely understood. Emerging evidence indicates that cellular metabolism can directly influence RNA processing by controlling the energy availability, metabolite concentrations, and post-translational modifications of spliceosomal proteins. In contrast to previous reviews that primarily examine how alternative splicing drives metabolic reprogramming or discuss individual metabolic pathways in isolation, this review integrates the reverse relationship—how cancer metabolism regulates the spliceosome itself. This mechanism-oriented narrative review examines the spliceosome as a metabolically responsive molecular machinery, with particular emphasis on pathways that generate therapeutically exploitable vulnerabilities. Methionine metabolism and S-adenosylmethionine availability regulate protein methylation through methionine adenosyltransferase 2A and protein arginine methyltransferase 5, while loss of methylthioadenosine phosphorylase creates a metabolically defined dependency that can be targeted pharmacologically. Polyamine-dependent metabolic shielding represents an emerging regulatory mechanism whereby polyamines can modulate the accessibility of selected spliceosomal phosphorylation sites and thereby influence alternative splicing; however, this mechanism has so far been demonstrated in a single prostate cancer study and has not yet been independently replicated. Additional metabolic inputs include adenosine triphosphate-dependent remodeling, divalent metal ions, acetyl-coenzyme A-dependent acetylation, and nutrient-sensitive glycosylation. These mechanisms collectively demonstrate that spliceosome activity is tightly integrated with cellular metabolic state. Therapeutically, MAT2A and PRMT5 inhibitors have entered clinical testing, whereas approaches targeting polyamine-dependent shielding, splicing kinases, or combined metabolic–spliceosomal vulnerabilities remain predominantly preclinical or conceptual.
Source: Medicina
Institution: Iuliu Hațieganu University of Medicine and Pharmacy
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,654
OpenAlex ID: W7225648840