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The mitochondrial toxin 3-nitropropionic acid (3-NP) is widely used to model HD-like pathologies. We investigated the therapeutic potential of coniferaldehyde (CFA), a natural phenolic compound with anti-inflammatory, antioxidant, and anti-radical properties, against 3-NP-induced neurodegeneration. Given the roles of oxidative stress, metabolic dysfunction, and neuroinflammation in HD, we hypothesize that CFA exerts neuroprotection by attenuating these processes via the Janus kinase 2\/signal transducer and activator of transcription 3 (JAK2\/STAT3) pathway - a novel target for CFA in HD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Neurological and behavioral deficits were assessed via neurological assessment scaling, rotarod, and open field tests. Nissl staining was performed to evaluate neuronal damage in the motor cortex and striatum. Dihydroethidium staining (DHE) was used to measure reactive oxygen species (ROS) levels, and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was conducted to detect apoptosis. Western blot assay and immunofluorescence staining were used to examine CFA\u2019s effect. Additionally, molecular docking was performed to analyze CFA\u2019s interaction with STAT3.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CFA treatment significantly improved motor function, preserved neuronal architecture, and reduced apoptosis, as confirmed by Nissl and TUNEL staining. CFA also decreased ROS levels and restored pyruvate kinase M2 (PKM2) expression, a key regulator of metabolic homeostasis. Consistently, CFA attenuated neuroinflammation by suppressing Glial Fibrillary Acidic Protein (GFAP) expression and proinflammatory cytokines Interleukin-6 (IL-6) and Interleukin-1 beta (IL-1\u03b2). Molecular docking studies revealed a strong binding affinity between CFA and STAT3, and western blot analysis showed reduced phosphorylation of STAT3, indicating modulation of the JAK2\/STAT3 signaling pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings demonstrate that CFA modulates oxidative, PKM2-mediated metabolic, and inflammatory pathways through the JAK2\/STAT3 axis, enhancing motor function and neuronal survival in a 3-NP model of HD. This multi-targeted mechanism highlights its potential as a disease-modifying therapy for advancing therapeutic strategies in HD and related neurodegenerative disorders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                    <jats:p>Neuroprotective mechanism of CFA in a 3-NP-induced HD model. 3-NP induces HD-like pathology in the motor cortex and striatum by inhibiting succinate dehydrogenase (Complex II), leading to ATP depletion, increased reactive oxygen species (ROS), neuroinflammation, apoptosis, PKM2 dysregulation, neurological impairments, and motor deficits. CFA treatment attenuates these pathological processes by reducing ROS and apoptosis, restoring PKM2 expression, and modulating glial activation and proinflammatory cytokines (IL-6 and IL-1\u03b2). In silico docking and in vivo analyses further show that CFA reduces phosphorylation of STAT3, suggesting suppression of the JAK2\/STAT3 pathway as a key mechanism of action. CFA promotes neurological and motor improvement, metabolic, and inflammatory homeostasis, supporting its potential as a disease-modifying therapeutic for HD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-025-01308-0","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T03:01:15Z","timestamp":1753930875000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Coniferaldehyde reverses 3-nitropropionic acid-induced Huntington\u2019s disease pathologies via PKM2 restoration and JAK2\/STAT3 inhibition"],"prefix":"10.1186","volume":"31","author":[{"given":"Ayooluwa Gabriel","family":"Ibiayo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peeraporn","family":"Varinthra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukundan","family":"Nagarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid Y","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"issue":"6","key":"1308_CR1","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","volume":"72","author":"A novel gene","year":"1993","unstructured":"A novel gene. 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