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Here, we constructed a high\u2010resolution, whole\u2010eye spatial multi\u2010omics atlas integrating Stereo\u2010seq transcriptomics and MALDI\u2010MSI\u2010based 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\u2013glial interactions were enhanced, revealing a shift from a neuron\u2010centered to an immunometabolic state. Within the ganglion cell layer (GCL), the primary pathological locus, we identified\n                    <jats:italic>Trem2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+<\/jats:italic>\n                    <\/jats:sup>\n                    microglia that expand in situ, establish close proximity to degenerating RGCs, and exhibit strong spatial association with dysregulated sphingolipid metabolism. Mechanistically, using\n                    <jats:italic>Trem2<\/jats:italic>\n                    knockout mice and microglia\u2010specific\n                    <jats:italic>Trem2<\/jats:italic>\n                    siRNA knockdown, we demonstrate that TREM2 directly binds to SPTLC2, the rate\u2010limiting enzyme of de novo sphingolipid biosynthesis, driving ceramide\u2010centric metabolic reprogramming that modulates the AKT\u2010mTOR signaling axis and amplifies inflammatory activation. Pharmacological inhibition of serine palmitoyl transferase (SPT) with myriocin reverses this cascade, protecting RGCs. Multi\u2010omics integration of human glaucoma aqueous humor datasets further reveals conserved upregulation of sphingolipid biosynthetic enzymes, sphingolipid metabolites, and lipid\u2010sensing immune effectors, offering preliminary translational clues. Collectively, our findings reveal that spatially defined immunometabolic remodeling\u2014in which\n                    <jats:italic>Trem2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+<\/jats:italic>\n                    <\/jats:sup>\n                    microglia are central\u2014converges on sphingolipid metabolism as a druggable regulatory axis, with the TREM2\u2010SPTLC2 interface thus emerging as a new therapeutic opportunity for retinal neurodegenerative diseases.\n                  <\/jats:p>","DOI":"10.1002\/imt2.70163","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T04:34:12Z","timestamp":1787286852000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial multi\u2010omics unveils sphingolipid metabolic reprogramming within the retinal pathological 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