{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T09:00:24Z","timestamp":1790240424497,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Int Endodontic J"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>This study explores how lipid metabolic reprogramming contributes to the pathogenesis of pulpitis and identifies key molecular targets involved in regulating inflammation, with the goal of developing metabolic interventions to preserve dental pulp vitality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>Primary human dental pulp cells (HDPCs) were stimulated with lipopolysaccharide (LPS) and subjected to integrated transcriptomic and metabolomic profiling to map inflammation\u2010associated metabolic shifts. Functional validation included linolenic acid (LA) supplementation (alone or combined with a Fatty Acid Synthase (FASN) inhibitor, TVB\u20102640), Nuclear receptor subfamily 4 group A member 1 (NR4A1) knockdown, cytokine\/NF\u2010\u03baB assessment (ELISA, Western blot), and lipid droplet\/FASN visualisation (immunofluorescence). FASN expression was confirmed in\u00a0vivo (rat pulpitis model). Key findings were verified in clinical pulpitis samples (histology, immunofluorescence, targeted fatty acid profiling).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LPS stimulation significantly upregulated FASN expression and induced lipid accumulation in HDPCs and rat pulpitis models (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Transcriptomic analysis revealed marked downregulation of NR4A1, while metabolomic profiling showed depletion of key anti\u2010inflammatory\/pro\u2010resolving PUFA precursors, including LA and \u03b3\u2010linolenic acid (GLA). Integrated transcriptomic\u2013metabolomic analysis identified LA as a metabolite with high centrality in the lipid metabolic network, and NR4A1 as a significantly downregulated transcription factor linked to multiple lipid\u2010related pathways. LA supplementation suppressed pro\u2010inflammatory cytokines (IL\u20101\u03b2, TNF\u2010\u03b1, phosphorylated NF\u2010\u03baB p65) and restored NR4A1 expression (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Combining LA with the FASN inhibitor TVB\u20102640 synergistically enhanced NR4A1 restoration and anti\u2010inflammatory effects (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). siRNA\u2010mediated NR4A1 knockdown abolished the benefits of LA. In human pulpitis tissues, FASN upregulation, NR4A1 downregulation, and elevated palmitic acid were observed (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001), along with increased levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study reveals a pathological FASN\u2013LA\u2013NR4A1 regulatory axis linking lipid metabolism to inflammatory amplification in pulpitis. Dual targeting of fatty acid synthesis and lipid depletion\u2014through FASN inhibition and LA supplementation\u2014attenuates inflammation via NR4A1\u2010dependent mechanisms. These findings lay the groundwork for metabolic approaches to modulate inflammation in endodontics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/iej.70026","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T07:47:01Z","timestamp":1756885621000},"page":"1913-1925","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Laboratory Investigation of Lipid Metabolic Reprogramming in Pulpitis: The Linolenic Acid\u2013\n                    <scp>FASN<\/scp>\n                    \u2013\n                    <scp>NR4A1<\/scp>\n                    Axis in Modulating Dental Pulp Inflammation"],"prefix":"10.1111","volume":"58","author":[{"given":"Mengqi","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Endodontics Shanghai Stomatological Hospital &amp; School of Stomatology, Fudan University  Shanghai P. R. China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University  Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Sui","sequence":"additional","affiliation":[{"name":"Department of Endodontics Shanghai Stomatological Hospital &amp; School of Stomatology, Fudan University  Shanghai P. R. China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University  Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changyi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endodontics Shanghai Stomatological Hospital &amp; School of Stomatology, Fudan University  Shanghai P. R. China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University  Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiangqiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Endodontics Shanghai Stomatological Hospital &amp; School of Stomatology, Fudan University  Shanghai P. R. China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University  Shanghai P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Endodontics Shanghai Stomatological Hospital &amp; School of Stomatology, Fudan University  Shanghai P. R. China"},{"name":"Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University  Shanghai P. R. 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