Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling

Spliceosomal dysfunction profoundly impacts cellular metabolism, yet mechanistic links between RNA splicing defects and metabolic rewiring remain limited. Here, we investigate Verheij syndrome (VRJS), a rare disease caused by mutations in the core splicing factor PUF60 . Using a Caenorhabditis elegans model, human cell lines, and patient-derived samples, we demonstrate that RNP-6/PUF60 deficiency disrupts splicing of genes governing one-carbon metabolism and phospholipid remodeling, culminating in impaired S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) cycling and phosphatidylcholine synthesis. These perturbations trigger the integrated stress response and compromise mTORC1 signaling, causing developmental and growth defects. Vitamin B12 (VB12) supplementation restores metabolic balance by reactivating SAM-dependent phospholipid remodelling and mTORC1 activity, effectively rescuing VRJS-like phenotypes. Similar metabolic responses arise from perturbations in other spliceosomal factors such as PRPF19/PRP-19, indicating a conserved mechanism across spliceosomopathies. Interestingly, we identify intron retention of the nhr-114/HNF4 transcription factor as a primary driver of growth defects, and restoring its splicing robustly suppresses these phenotypes. Our findings establish a mechanistic connection between RNA splicing and lipid metabolism, implicating VB12-dependent one-carbon metabolism as a metabolic modulator with broad implications for spliceosome-related diseases, and suggesting VB12 as a potential strategy to mitigate VRJS-related anomalies.