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Using induced pluripotent stem cell (iPSC)\u2010derived motor neurons, astrocytes, and microglia from\n                    <jats:italic>C9orf72<\/jats:italic>\n                    patients and their isogenic controls, we investigated metabolic changes at the single\u2010cell level under basal and inflammatory conditions. Our results showed that microglia are particularly susceptible to metabolic disturbances. While\n                    <jats:italic>C9orf72<\/jats:italic>\n                    motor neurons exhibited impaired mitochondrial respiration and reduced ATP production,\n                    <jats:italic>C9orf72<\/jats:italic>\n                    microglia presented pronounced increases in glycolytic activity and oxidative stress, accompanied by the upregulation of the expression of key metabolic enzymes. These metabolic changes in microglia were exacerbated by inflammatory stimuli. To investigate how these changes affect the broader cellular environment, we developed a human iPSC\u2010derived triculture system comprising motor neurons, astrocytes, and microglia. This model revealed increased metabolic activity in all cell types and highlighted that microglia\u2010driven metabolic reprogramming in astrocytes contributes to the vulnerability of motor neurons under inflammatory conditions. Our findings highlight the central role of microglia in driving metabolic dysregulation and intercellular crosstalk in ALS pathogenesis and suggest that targeting metabolic pathways in immune cells may provide new therapeutic avenues.\n                  <\/jats:p>","DOI":"10.1002\/glia.70080","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T12:36:21Z","timestamp":1756730181000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<i>C9orf72<\/i>\n                    Repeat Expansion Induces Metabolic Dysfunction in Human\n                    <scp>iPSC<\/scp>\n                    \u2010Derived Microglia and Modulates Glial\u2010Neuronal Crosstalk"],"prefix":"10.1002","volume":"74","author":[{"given":"Marika","family":"Mearelli","sequence":"first","affiliation":[{"name":"Hertie Institute for Clinical Brain Research University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"German 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