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Oligodendrocyte precursor cells (OPCs), which generate mature oligodendrocytes (OLs) forming the myelin sheath, are responsive to metabolic and redox signals. Despite increasing interest in lipid metabolism and mitochondrial dynamics as regulators of OPC fate, the effects of PA remain unclear. This study investigates the biphasic, dose\u2010dependent effects of PA on OPCs using the oligodendrocyte precursor MO3.13 cell line and employs rat organotypic slice cultures to evaluate the effects of non\u2010toxic PA doses under pathological conditions and on axonal (re)\u2010myelination. In MO3.13 cells, high\u2010dose PA (100\u2009\u00b5M) induces mitochondrial fragmentation and caspase\u20107 activation, accompanied by reduced mitofusin\u20102 (MFN2) and phosphorylated dynamin\u2010related protein 1 at Ser616 (p\u2010DRP1), indicating altered fusion\u2010fission balance and impaired reactive oxygen species (ROS) generation. In contrast, low\u2010dose PA (25\u2009\u00b5M) triggers a protective response involving nuclear factor erythroid 2\u2013related factor 2 (Nrf2) activation and upregulation of antioxidant and lipid\u2010regulatory genes (glutamate\u2013cysteine ligase modifier subunit [GCLM], NAD(P)H dehydrogenase [quinone] 1 [NQO1], peroxisome proliferator\u2010activated receptor gamma [PPAR\u03b3], and cluster of differentiation 36 [CD36]) resulting in reduced intracellular ROS and enhanced lipid mobilization. PA 25\u2009\u00b5M promotes OPC differentiation by inhibiting migration and cell cycle progression and increasing myelin basic protein (MBP) and proteolipid protein (PLP) expression. Notably, early exposure (1 day) favors mitochondrial fusion, whereas prolonged exposure (4 days) shows a physiological shift to fission. PA 25\u2009\u00b5M prevents neurodegeneration in hippocampal organotypic slice cultures exposed to a neuroinflammatory insult. In cerebellar organotypic slice cultures, PA 25\u2009\u00b5M enhances axonal myelination and accelerates remyelination following lysolecithin\u2010induced demyelination. These findings highlight the physiological relevance of low\u2010dose PA in modulating OLs.<\/jats:p>","DOI":"10.1002\/jcp.70145","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T16:31:50Z","timestamp":1770654710000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Dose\u2010Dependent Biphasic Effect of Palmitic Acid on Oligodendrocyte Function: Impacts on Viability, Differentiation, and Myelination"],"prefix":"10.1002","volume":"241","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7988-9208","authenticated-orcid":false,"given":"Anna","family":"Palmiero","sequence":"first","affiliation":[{"name":"Department of Clinical Medicine and Surgery University of Naples \u201cFederico II\u201d Naples 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