{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T11:56:11Z","timestamp":1788436571914,"version":"build-2803163510"},"reference-count":60,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;amp;D Transl Res &amp;amp; Clin Interv"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      Alzheimer's disease (AD) is driven by interrelated pathologies, including the accumulation of amyloid \u03b2 (A\u03b2), tau pathology, chronic neuroinflammation, and oxidative stress (OS). These pathological processes collectively lead to progressive neurodegeneration. The transcription factor specificity protein 1 (\n                      <jats:italic>SP1<\/jats:italic>\n                      ) functions as a key transcriptional regulator in AD pathogenesis. By binding to GC\u2010box elements,\n                      <jats:italic>SP1<\/jats:italic>\n                      promotes A\u03b2 production and tau hyperphosphorylation. It also activates microglia, perpetuating neuroinflammation; disrupts oxidative balance; and ultimately induces neuronal death through ferroptosis and apoptosis. Furthermore, environmental toxins exacerbate AD progression by enhancing\n                      <jats:italic>SP1<\/jats:italic>\n                      \u2010DNA binding activity via epigenetic mechanisms such as DNA methylation and histone modifications.\n                      <jats:italic>SP1<\/jats:italic>\n                      activity is tightly controlled by diverse post\u2010translational modifications, which adds another layer of complexity to its function. Small\u2010molecule inhibitors, natural compounds, and epigenetic interventions can modulate the\n                      <jats:italic>SP1<\/jats:italic>\n                      \u2010regulated network, thereby ameliorating key pathological features and demonstrating broad therapeutic potential. Future efforts must address developing brain\u2010targeted delivery systems and precise epigenetic editors for effective clinical translation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>SP1<\/jats:italic>\n                            functions as a master transcriptional hub in Alzheimer's disease, simultaneously driving amyloid beta production, tau hyperphosphorylation, neuroinflammation, oxidative stress, and ferroptotic cell death.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Environmental toxins epigenetically activate\n                            <jats:italic>SP1<\/jats:italic>\n                            via altered DNA methylation and histone modifications, establishing a molecular link between external risk factors and late\u2010onset Alzheimer's pathogenesis.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Post\u2010translational modifications and microRNAs tightly regulate\n                            <jats:italic>SP1<\/jats:italic>\n                            activity; their dysregulation in AD amplifies pathogenic gene expression networks.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Small\u2010molecule inhibitors and natural compounds targeting\n                            <jats:italic>SP1<\/jats:italic>\n                            demonstrate multi\u2010pathway therapeutic potential in preclinical Alzheimer's models.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Cell\u2010type\u2013specific\n                            <jats:italic>SP1<\/jats:italic>\n                            functions, compensatory upregulation of\n                            <jats:italic>SP3\/SP4<\/jats:italic>\n                            family members, and limited blood\u2013brain barrier penetration present major challenges for clinical translation.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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