Temporal dynamics of mRNA translation dysregulation and codon decoding during murine stroke evolution.

Ischemic stroke triggers rapid molecular programs that are poorly captured by transcriptomics. We present a temporal ribosome-profiling atlas of mouse ischemic brain and uncover a staged translational injury response. During the hyperacute phase, mRNA abundance and ribosome occupancy are uncoupled, translation transiently shifts toward GC-ending codons, and hundreds of transcripts show a burst of stop-codon readthrough with 3'UTR ribosome footprints, consistent with termination stress. Machine-learning analysis identified pre-stop ribosome queuing and frame-specific 3'UTR ribosome usage, with contributions from local RNA structure, as key determinants of readthrough dynamics. From 6-24 h, translation exhibits progressive A-site pausing and widespread disruption of ribosomal reading frame. A subset of events localizes to discrete CDS loci with characteristic sequence/structure signatures and predicted PTC/NMD propensity, whereas most coincide with extensive alternative ORF usage and uORF remodeling of translation. These data reveal translational mechanisms that evolve across stroke and provide a framework to interrogate translation dysregulation in diseases.