Transcriptomic signatures of gray matter volume loss in cerebral small vessel disease

White matter hyperintensities (WMHs) are a hallmark imaging sign of cerebral small vessel disease (CSVD) and are closely linked to motor and cognitive deficits. Using voxel‑based morphometry (VBM) together with spatial transcriptomics, this study explored the altered molecular pathways underlying the reduction in gray matter volume (GMV) associated with WMHs. We included 25 patients with WMHs and 26 healthy controls. The VBM analysis was used to identify brain regions with reduced GMV. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were then performed using spatial transcriptomic data from the Allen Human Brain Atlas (AHBA) to explore the underlying molecular pathways. Compared to healthy controls, patients with WMHs exhibited significantly reduced GMV in several key brain regions (p < 0.01, cluster-level corrected). These GMV reductions were widely distributed across the frontal, parietal, temporal, and occipital lobes, as well as the cingulate cortex and cerebellum. A total of 597 genes significantly associated with GMV loss were enriched in core neurobiological pathways, including protein synthesis, RNA metabolism, intracellular protein transport, and protein homeostasis. GO analysis revealed ribosome- and translation-related terms as the most significantly enriched across all three domains—biological process (BP), molecular function (MF), and cellular component (CC)—with structural constituent of ribosome and cytosolic ribosome being the most prominent in the MF and CC categories, respectively. Consistently, KEGG pathway analysis highlighted significant enrichment of both the ribosome and spliceosome pathways, further supporting the central role of cellular stress responses, DNA repair, and lysosomal function in the observed GMV-associated genes. WMHs-related gray matter atrophy may be spatially associated with coordinated perturbations in RNA metabolism and ribosome-mediated translation, together with dysregulated DNA metabolic processes and altered cellular stress responses.