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Integrated multi\u2010source data and machine learning identified ACT and FA as BDD's core components, mediating therapeutic effects via neurotransmitter regulation and inflammatory suppression. Co\u2010administering ACT and FA at their BDD ratio replicated the parent formulation\u2019s anti\u2010inflammatory and antidepressant effects. Both compounds stabilized Nrf2, with ACT exhibiting greater potency. Crucially, the ACT\/FA combination shifted microglia from pro\u2010inflammatory M1 to neuroprotective M2 phenotypes via dual activation of Nrf2 and ROR\u03b3t pathways. Pharmacological inhibition or genetic knockdown of Nrf2 abolished these effects, confirming its central role. This dual mechanism concurrently rectifies neuroinflammation at its microglial source and impedes peripheral immune factor invasion, effectively restoring neuroimmune homeostasis in depression. These findings provide a mechanistic foundation for optimizing herbal\u2010derived combinatorial therapies targeting microglial polarization.<\/jats:p>","DOI":"10.1002\/advs.202503889","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T08:59:20Z","timestamp":1755680360000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Synergistic Modulation of Microglial Polarization by Acteoside and Ferulic Acid via Dual Targeting of Nrf2 and ROR\u03b3t to Alleviate Depression\u2010Associated Neuroinflammation"],"prefix":"10.1002","volume":"12","author":[{"given":"Dongjing","family":"Guo","sequence":"first","affiliation":[{"name":"Shandong Co\u2010Innovation Center of Classic TCM Formula Shandong University of Traditional Chinese Medicine  Jinan 250355 P. R. 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