Metabolic Reprogramming by Andrographolide: Enhanced Pentose Phosphate Pathway and Antioxidant Capacity in Cortical Astrocytes

<b>Background/Objectives:</b> Astrocytes are key regulators of brain energy homeostasis, integrating glucose metabolism with antioxidant support for neuronal function. Dysregulation of these processes contributes to neurodegenerative diseases, including Alzheimer's disease. Andrographolide, a bioactive diterpenoid from <i>Andrographis paniculata</i>, has been reported to exert neuroprotective effects through the modulation of Wnt/β-catenin signaling and neuronal metabolism; however, its actions on astrocytic metabolic pathways remain insufficiently characterized. <b>Methods:</b> Here, we investigated the effects of andrographolide on metabolic and redox parameters in primary mouse cortical astrocytes. <b>Results:</b> Andrographolide increased glucose uptake and antioxidant capacity without affecting AMPK activation or the activity of core glycolytic enzymes. Instead, it selectively enhanced glucose-6-phosphate dehydrogenase activity, promoting glucose flux through the pentose phosphate pathway in a partially Wnt-dependent manner. This metabolic reprogramming was associated with increased NADPH availability and glutathione levels, together with a reduced ATP/ADP ratio, consistent with a shift toward redox maintenance rather than maximal energy production. <b>Conclusions:</b> Collectively, these findings highlight astrocytic metabolic plasticity as a relevant and underexplored target of andrographolide and support the concept that natural compounds can enhance brain resilience by modulating glial redox metabolism.