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This work aimed at clarifying the function of senescence\u2010related genes (SRGs) in PD and investigating their molecular underpinnings, as well as their potential diagnostic and therapeutic significance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      By integrating bioinformatics with experimental validation, the CellAge database provided 278 SRGs for this study. A total of 2925 differentially expressed genes (DEGs) and 31 differentially expressed SRGs (DESRGs) were identified, which are mainly involved in signaling pathways, including nuclear factor kappa light chain enhancer of activated B cells (NF\u2010\u03baB) and interleukin 17 (IL\u201017). Through protein\u2013protein interaction (PPI) network analysis, 10 hub genes were identified, such as\u2009\n                      <jats:italic>IRF7<\/jats:italic>\n                      ,\u2009\n                      <jats:italic>IFNG<\/jats:italic>\n                      , and\u2009\n                      <jats:italic>BCL6<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In PD mouse and MN9D cell models by\u2009D\u2010galactose (D\u2010gal) and 1\u2010methyl\u20104\u2010phenyl\u20101,2,3,6\u2010tetrahydropyridine (MPTP), combined treatment (D\u2010gal + MPTP) synergistically reduced tyrosine hydroxylase (TH) expression, promoted \u03b1\u2010synuclein (\u03b1\u2010syn) aggregation, aggravated cellular senescence, and caused significant upregulation of\u2009\n                      <jats:italic>IRF7<\/jats:italic>\n                      , whereas\u2009\n                      <jats:italic>IRF7<\/jats:italic>\n                      \u2009small interfering RNA (siRNA) intervention reversed senescence\u2010 and PD\u2010related pathological changes. Molecular docking analyses identified candidate small molecules targeting hub genes, including fostamatinib and ropsacitinib. In\u2009vitro experiments provided preliminary support that these compounds modulated SYK and TYK2 proteins and alleviated pathological phenotypes in cellular models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Overall, this study demonstrates that\u2009D\u2010gal\u2010induced aging\u2010like stress accelerates PD\u2010related pathological progression by activating multiple signaling pathways, including JAK\u2013STAT, AGE\u2013RAGE, and NF\u2010\u03baB, thereby promoting inflammation, oxidative stress, and neuronal dysfunction. Key genes including\u2009\n                      <jats:italic>IRF7<\/jats:italic>\n                      \u2009may serve as candidate biomarkers, providing preliminary evidence for the role of senescence\u2010like stress in PD pathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ame2.70240","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T08:41:12Z","timestamp":1782895272000},"page":"1761-1781","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of senescence\u2010related genes in Parkinson's disease reveals candidate therapeutic targets and pathological processes"],"prefix":"10.1002","volume":"9","author":[{"given":"Haojie","family":"Wu","sequence":"first","affiliation":[{"name":"Institute for Brain Sciences Research, Center for Translational Neuromedicine, School of Life Sciences Henan University  Kaifeng 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