STAT1 sets microglial neutral-lipid content independently of lipid-handling transcriptional programs

Inflammatory activation and lipid remodeling are linked features of microglial states, but how inflammatory transcription factors shape microglial lipid handling is unclear. Here we show that STAT1 sets neutral-lipid content in microglia through a route not predicted by lipid-handling transcription. Acute STAT1 depletion in primary microglia lowered neutral-lipid content while lipid-uptake and lipid-storage programs were induced, and interferon-γ activation moved inflammatory transcription in the opposite direction yet lowered lipid content alike. Single-cell transcriptomic and chromatin profiling of Stat1- and Irf1-deficient mice showed that STAT1 and IRF1 organize overlapping inflammatory and lipid-handling programs, with genome-wide accessibility changes that did not predict transcriptional output at individual lipid-handling loci. Microglia co-expressing STAT1 and APOE recurred across Alzheimer’s disease and multiple sclerosis datasets. Transcriptional program engagement is therefore separable from cellular lipid state, and lipid-handling gene expression cannot be read as a proxy for microglial lipid content.