Abstract Retinal ischemia‐reperfusion (RIR) injury is a central mechanism underlying irreversible vision loss in glaucoma and other retinal diseases, yet the spatial organization of the pathogenic microenvironment remains poorly understood. Here, we constructed a high‐resolution, whole‐eye spatial multi‐omics atlas integrating Stereo‐seq transcriptomics and MALDI‐MSI‐based metabolomics to capture the early molecular events in the RIR mouse model. Spatially, retinal ganglion cell (RGC) interactions with surrounding cells were markedly reduced after injury, whereas immune–glial interactions were enhanced, revealing a shift from a neuron‐centered to an immunometabolic state. Within the ganglion cell layer (GCL), the primary pathological locus, we identified Trem2 + microglia that expand in situ, establish close proximity to degenerating RGCs, and exhibit strong spatial association with dysregulated sphingolipid metabolism. Mechanistically, using Trem2 knockout mice and microglia‐specific Trem2 siRNA knockdown, we demonstrate that TREM2 directly binds to SPTLC2, the rate‐limiting enzyme of de novo sphingolipid biosynthesis, driving ceramide‐centric metabolic reprogramming that modulates the AKT‐mTOR signaling axis and amplifies inflammatory activation. Pharmacological inhibition of serine palmitoyl transferase (SPT) with myriocin reverses this cascade, protecting RGCs. Multi‐omics integration of human glaucoma aqueous humor datasets further reveals conserved upregulation of sphingolipid biosynthetic enzymes, sphingolipid metabolites, and lipid‐sensing immune effectors, offering preliminary translational clues. Collectively, our findings reveal that spatially defined immunometabolic remodeling—in which Trem2 + microglia are central—converges on sphingolipid metabolism as a druggable regulatory axis, with the TREM2‐SPTLC2 interface thus emerging as a new therapeutic opportunity for retinal neurodegenerative diseases.
Yun-Hong Shi, Jinpei Lin, Yi Wu et al.· iMeta· 0 citations
ABSTRACT Retinal ischemia-reperfusion injury (RIR) is the main pathogenic mechanisms of acute glaucoma, diabetic retinopathy, central retinal vein occlusion. As a common post-transcriptional modification of eukaryotic RNAs, N6-methyladenosine (m6A) is associated with the pathogenesis of different diseases, including angiogenesis, through the regulation of RNA metabolism and functions. The aim of this study was to identify the potential relevance of m6A RNA methylation in pathogenesis of RIR. A total of 10,851 mRNAs and 23,270 associated m6A methylation modified peaks were identified in the RIR group. Similarly, 10,391 mRNAs and 22,935 associated m6A methylation modified peaks were detected in the Sham group. MeRIP-seq identified 3,871 RIR-specific m6A peaks and 3,624 Sham-specific m6A peaks, in addition to 19,399 shared peaks between groups. Gene ontology (GO) analysis showed that hypermethylated mRNAs were enriched in cellular process, cellular anatomical entity, and binding, while hypomethylated mRNAs were enriched in synaptic signaling, synapse, and gated channel activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that hypermethylated mRNAs were involved in tight junction, hippo signaling pathway, and PI3K-Akt signaling pathway, while hypomethylated mRNAs were involved in Neuroactive ligand-receptor interaction, glutamatergic synapses, cholinergic synapses. Joint analysis identified mRNAs with differential m6A methylation and expression simultaneously. Among them, the expression patterns of Irx4, Kdr, and Lyz2 were confirmed by RT-qPCR to be consistent with the sequencing results. The results revealed an altered m6A epitranscriptome in RIR retinas. These methylated RNAs may act as novel modulators and targets in RIR.
It is shown that the NAD+ precursor NMN protects against retinal degeneration by improving mitochondrial function in MERTK-associated models, offering potential therapeutic insights.