Background <p>Microglial metabolic dysfunction is increasingly recognized as a key driver of neuroinflammation in Alzheimer’s disease (AD). However, the specific metabolic regulators linking lipid metabolism to pathological activation remain poorly defined.</p> Methods <p>We performed integrative transcriptomic analysis on four human AD brain datasets to identify core metabolic hubs. Sprouty homolog 1 (SPRY1) expression was examined in human post-mortem tissues, and its functional role was validated in primary microglia, <i>Drosophila</i>, and <i>APP/PS1-21</i> mice using genetic knockdown, behavioral assays, and histological analysis. Moreover, we employed co-immunoprecipitation, mass spectrometry, and metabolic flux assays to elucidate the underlying pathways.</p> Results <p>We identified SPRY1 as a key hub gene upregulated in the hippocampus of AD patients and mouse models. SPRY1 was predominantly expressed in plaque-associated microglia, and specifically correlated with advancing age, Aβ load and Braak stage. Functionally, microglial SPRY1 knockdown enhanced Aβ phagocytosis, reduced pro-inflammatory cytokines, and protected neurons from Aβ-induced damage in vitro. In vivo, glial-specific knockdown of the SPRY1 homolog <i>sty</i> rescued cognitive and motor deficits in AD flies, while microglia-specific knockdown in mice reduced amyloidosis and neuroinflammation. Mechanistically, SPRY1 acted as a metabolic switch by retaining fatty acid transport protein 3 (FATP3) on the endoplasmic reticulum (ER). This interaction blocked FATP3 translocation to mitochondria, thereby reducing fatty acid oxidation (FAO) and promoting lipid droplet (LD) accumulation, which drives a microglial pro-inflammatory phenotype.</p> Conclusions <p>This study unveils a novel SPRY1-FATP3 retention mechanism that links impaired fatty acid metabolism to neuroinflammation. Targeting this axis represents a promising strategy to reprogram microglial metabolism and provide neuroprotection in AD.</p> Graphical Abstract <p></p>