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However, how these processes are integrated at the molecular level remains unclear. Here, we propose that activity-dependent lipid flux represents a central mechanism linking these processes. Saturated free\u00a0fatty acids (sFFAs) released from membrane phospholipids, triglycerides, or from extracellular uptake can be activated to acyl-CoA and directed to mitochondrial \u03b2-oxidation and synaptic protein lipidation. These represent two emerging pathways adding to the complexity of roles played by sFFAs, including membrane fluidity and receptor activation. Recent work identifies DDHD2 as a mechanistic entry point into this broader synaptic lipid network. We position DDHD2-dependent lipid mobilisation in the wider context of glia-neuron lipid transfer and ApoE\/sortilin-dependent fatty acid uptake. Key unresolved questions include the source and fate of fatty acids, the relative contribution of \u03b2-oxidation versus glycolysis to ATP production, and whether these pathways are altered in neurodegenerative disease.<\/jats:p>","DOI":"10.1038\/s44318-026-00944-4","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T15:30:47Z","timestamp":1792596647000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lipid-fuelled synaptic plasticity: integrating membrane turnover, \u03b2-oxidation, and protein lipidation"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1296-2023","authenticated-orcid":false,"given":"Saber H","family":"Saber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2304-8763","authenticated-orcid":false,"given":"Sevannah A","family":"Steeves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yara","family":"Abosnwber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6515-9157","authenticated-orcid":false,"given":"Tristan P","family":"Wallis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6400-1107","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9ric A","family":"Meunier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,21]]},"reference":[{"key":"944_CR1","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/s44318-024-00030-7","volume":"43","author":"IO Akefe","year":"2024","unstructured":"Akefe IO, Saber SH, Matthews B, Venkatesh BG, Gormal RS, Blackmore DG, Alexander S, Sieriecki E, Gambin Y, Bertran-Gonzalez J (2024) The DDHD2-STXBP1 interaction mediates long-term memory via generation of saturated free fatty acids. 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