Synergistic Modulation of Microglial Polarization by Acteoside and Ferulic Acid via Dual Targeting of Nrf2 and RORγt to Alleviate Depression‐Associated Neuroinflammation

Abstract Acteoside (ACT) and ferulic acid (FA), the principal bioactive constituents of Baihe Dihuang decoction (BDD), possess established anti‐inflammatory and antidepressant properties, but their combined effect on microglial phenotype modulation remains unclear. Integrated multi‐source data and machine learning identified ACT and FA as BDD's core components, mediating therapeutic effects via neurotransmitter regulation and inflammatory suppression. Co‐administering ACT and FA at their BDD ratio replicated the parent formulation’s anti‐inflammatory and antidepressant effects. Both compounds stabilized Nrf2, with ACT exhibiting greater potency. Crucially, the ACT/FA combination shifted microglia from pro‐inflammatory M1 to neuroprotective M2 phenotypes via dual activation of Nrf2 and RORγt 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‐derived combinatorial therapies targeting microglial polarization.