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Across the studies included in this Research Topic, neuroinflammation is no longer viewed as a simple or unidirectional process. Instead, it is increasingly understood as a complex and context-dependent network of biological responses, that involve multiple glial states, signals from peripheral immune system, metabolic and oxidative conditions, and different disease stages.Moreover, the field is moving away from the idea that individual inflammatory molecules, such as single cytokines, are solely responsible for disease processes.Rather, researchers are adopting a systems-level perspective, that examine how multiple pathways interact to shape the overall inflammatory response and how interventions targeting these elements may modulate and mitigate neuroinflammation.This shift reflects the understanding that neuroinflammation operates through interconnected regulatory networks rather than isolated signaling events.Consequently, therapeutic strategies must consider not only the direct effects of targeting a particular molecule or signaling pathway, but also the possibility of collateral biological outcomes triggered by compensatory mechanisms or unintended effects elsewhere in the network.A central framework for this topic is provided by the mini-review by Müller et al., which highlights the dual nature of neuroinflammation within the interconnected environment of the brain. Rather than being activated in a simple on-off manner, microglia and astrocytes undergo a series of regulatory transitions. These changes are orchestrated by complex cytokine signaling pathways, receptor-mediated interactions, metabolic signals from the cellular environment, and continuous feedback from neurons. This dynamic and multi-layered regulation illustrates that neuroinflammation is an adaptive network process shaped by different players within the brain.In this view, inflammation is not merely an output of pathology, it is also an adaptive regulatory system, that contributes to tissue repair and neural resilience but becomes maladaptive when inflammatory resolution fails or when persistent stimuli, such as aging, protein aggregation or cellular stress lock glia cells into chronic A clear example of this multi-target approach is the study by Liu et al.examining a combination therapy of curcumin and Glycyrrhiza glabra in an Alzheimer's disease (AD) model. Using a D-galactose/sodium nitrite-induced mouse model, the authors reported that curcumin alone modestly improved spatial learning and reduced IL-6 levels, while Glycyrrhiza glabra alone showed limited effects. In contrast, the combined treatment produced the most pronounced behavioral improvements and broader biochemical impact, including the reduction of proinflammatory cytokines and the increasement of antioxidant capacity. The authors suggest that modulation of TLR4/MyD88/NF-κB signaling and redox pathways may underlie these observed anti-inflammatory and antioxidant effects, although direct assessment of pathway activation remains to be performed.Mechanistic precision is further illustrated in the Parkinson's disease (PD) study on DJ-1, a multifunctional protein implicated in PD pathogenesis, and its role in microglial NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation. Miao et al. reported that Inflammatory stimuli increase DJ-1 levels, whereas reduction of DJ-1 suppresses NLRP3 inflammasome signaling (but not NLRC4 or AIM2), as shown by decreased caspase-1 activity and interleukin-1β (IL-1β) production. DJ-1 binds to and stabilizes NLRP3, preventing its autophagic degradation, a mechanism confirmed using autophagy modulators. These findings suggest that modulation of DJ-1 in microglia may attenuate neuroinflammation and confer neuroprotective effects. It will also be important to assess whether targeting this interaction can preserve beneficial microglial functions, such as phagocytosis, while preventing harmful IL-1β-driven inflammatory responses. Addressing these points will help clarify how inflammasome-targeted strategies might promote tissue repair and prevent chronic neuroinflammation.