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Emerging evidence, however, identifies PPAR\u03b3 as a central immunometabolic regulator in the central nervous system (CNS), coordinating mitochondrial function, neuroinflammation, synaptic plasticity, and neurovascular integrity. Beyond its classical metabolic actions, PPAR\u03b3 regulates microglial activation, astrocytic inflammatory responses, oxidative stress, and mitochondrial biogenesis, thereby influencing neuronal resilience and circuit stability. This narrative review synthesizes knowledge of PPAR\u03b3 structure, activation, CNS distribution, endogenous ligands, and synthetic agonists, including thiazolidinediones and selective modulators. We highlight how PPAR\u03b3 controls transcriptional programs related to energy homeostasis, inflammatory signaling, including NF \u03baB dependent pathways, and blood brain barrier function. Attention is devoted to synaptic remodeling and plasticity, positioning PPAR\u03b3 as a molecular bridge between metabolic state and neuronal adaptability. We propose that PPAR\u03b3 signaling dysregulation represents a convergent mechanism in neurodegenerative disorders, including Alzheimer\u2019s disease, Parkinson\u2019s disease, and adrenoleukodystrophy; psychiatric conditions, such as depression and anxiety; and neurooncological processes. Integrating evidence across these conditions supports PPAR\u03b3 as a master regulator of neuroimmune metabolic coupling in the brain. Finally, we discuss translational challenges and opportunities, including brain penetrant, functionally selective ligands, clarification of cell type specific signaling, and expansion of rigorous clinical trials. Integrating mechanistic, preclinical, and clinical trial evidence, this review critically examines the therapeutic potential of PPAR\u03b3 across neurodegenerative, psychiatric, and neurooncological CNS conditions, while identifying priorities for future therapeutic development in diverse brain disorders.<\/jats:p>","DOI":"10.1007\/s11064-026-04908-2","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:10:59Z","timestamp":1791817859000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PPAR\u03b3 Signaling in the Central Nervous System: A Review of the Implications in Synaptic Plasticity, Neuroinflammatory and Neoplastic Processes"],"prefix":"10.1007","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5398-1277","authenticated-orcid":false,"given":"Vanessa Camylla Bernardo","family":"de Oliveira Maciel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7087-5742","authenticated-orcid":false,"given":"Josenilda","family":"de Moura Arruda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2988-6787","authenticated-orcid":false,"given":"Ryan Cordeiro","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0163-3833","authenticated-orcid":false,"given":"Michelle Melgarejo","family":"da Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"key":"4908_CR1","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.ijdevneu.2019.01.007","volume":"77","author":"M Saito","year":"2019","unstructured":"Saito M, Saito M, Das BC (2019) Involvement of AMP-activated protein kinase in neuroinflammation and neurodegeneration in the adult and developing brain. 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