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While prior work has linked\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      expression to higher-grade meningiomas and treatment resistance, the metabolic phenotype of\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      activation remains unexplored in meningioma.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed single-cell RNA sequencing on NOTCH3\u2009+\u2009human meningioma cell lines. Using the CH157-MN meningioma cell model, we overexpressed\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      intracellular domain (ICD) and performed untargeted metabolomic, lipidomic, and bulk RNA sequencing analyses as well as functional metabolic assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We show that\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      mediates a metabolic shift towards fatty acid oxidation (FAO), depleting lipid availability and conferring resistance to ferroptosis. Single-cell RNA sequencing revealed a correlation with CD36, a key fatty acid transporter. Furthermore, patient-derived primary meningioma lines stratified by\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      expression confirmed higher\n                      <jats:italic>CD36<\/jats:italic>\n                      expression and increased maximal mitochondrial respiration in\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      -high cells in the presence of palmitate, supporting enhanced FAO.\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      ICD overexpression (OE) exhibited depletion of fatty acid pools, alongside transcriptional upregulation of canonical FAO genes. Functional mitochondrial assays confirmed elevated oxidative respiration in the presence of palmitate compared with controls. Additionally,\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      OE cells exhibit increased resistance to RSL3-induced ferroptosis, a phenotype that was reversed with CPT1 inhibition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These data establish a link between\n                      <jats:italic>NOTCH3<\/jats:italic>\n                      signaling, lipid metabolic reprogramming, and ferroptosis evasion in aggressive meningioma cells. This metabolic shift may contribute to the malignant behavior observed in\n                      <jats:italic>NOTCH3\u2009+<\/jats:italic>\n                      \u2009meningiomas, offering new insight into the biochemical vulnerabilities of these tumors.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11060-025-05208-5","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T12:21:57Z","timestamp":1757420517000},"page":"979-991","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["NOTCH3 drives fatty acid oxidation and ferroptosis resistance in aggressive meningiomas"],"prefix":"10.1007","volume":"175","author":[{"given":"Nishanth S.","family":"Sadagopan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateo","family":"Gomez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashwat","family":"Tripathi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah K.","family":"Billingham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan L.","family":"DeLay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha A.","family":"Cady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harrshavasan T. 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