Molecular Mechanisms of Plant Secondary Metabolites in Modulation of ROS-mediated Microglial Activation and Neuroinflammation: Special Emphasize to Quercetin.

Neuroinflammation is a central pathogenic mechanism in numerous neurological disorders, with microglia playing a pivotal role in coordinating immune responses through tightly regulated redox, metabolic, and inflammatory signaling pathways. While transient microglial activation supports tissue homeostasis and repair, persistent activation promotes excessive production of reactive oxygen and nitrogen species (ROS/RNS), pro-inflammatory mediators, and lipid-derived inflammatory signals, driving chronic neuroinflammation and neurodegeneration. Accordingly, modulation of microglial activation has emerged as an attractive therapeutic strategy. Plant-derived extracts and phytochemicals represent a remarkable source of bioactive molecules such as quercetin, which are able to concomitantly modulate multiple pathways involved in microglial activation. Over the past two decades, numerous studies have investigated their effects using immortalized murine BV-2 cells and, to a lesser extent, primary microglia. Despite differences between these experimental models, current evidence reveals a striking convergence of molecular mechanisms. Plant-derived metabolites consistently attenuate microglial activation through inhibition of the NF-κB and MAPK signaling pathways, activation of the Nrf2/HO-1 antioxidant axis, suppression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokine production, while limiting oxidative stress and lipid peroxidation. Emerging evidence further indicates that these compounds regulate microglial phenotypic plasticity, mitochondrial function, immunometabolic reprogramming, and, potentially, peroxisomal metabolism and mitochondria-peroxisome crosstalk, thereby extending their actions well beyond conventional antioxidant activity. This review critically examines the molecular mechanisms by which plant-derived extracts and phytochemicals regulate microglial function, with particular emphasis on the interconnected networks linking redox homeostasis, inflammatory signaling, lipid metabolism, and organelle communication.