Caffeic acid restores neurogenesis and synaptic integrity under glucolipotoxic stress by suppressing inflammation and pyroptosis

Diabetes mellitus is frequently associated with cognitive dysfunction, primarily attributed to impaired hippocampal neurogenesis, oxidative stress, inflammation, and pyroptosis. Caffeic acid (CA), a dietary polyphenol, has demonstrated antioxidant and neuroprotective effects. This study evaluated the protective role of CA under diabetic-like conditions using an in vitro glucolipotoxicity model in HT-22 hippocampal neurons exposed to high glucose and oleic acid (HG + OA). CA was administered at low (5 µM) and high (25 µM) concentrations prior to HG + OA treatment. CA significantly enhanced neuronal viability and restored the expression of neurogenesis markers (Nestin, DCX, NeuN) and synaptic proteins (PSD-95, Synaptophysin). Furthermore, CA elevated antioxidant enzyme levels (Nrf2, catalase, SOD-1), regulated apoptosis through increased Bcl-2 and decreased BAX expression, and attenuated inflammatory responses. Pyroptosis was also suppressed, as evidenced by reduced gasdermin D (GSDMD) expression. These findings suggest that CA confers multifactorial neuroprotection against glucolipotoxic injury, and may serve as a dietary modulator for mitigating diabetes-associated cognitive decline in vitro. CA promotes adult hippocampal neurogenesis (AHN) through activation of the BDNF/TrkB/Akt/mTOR/CREB signaling pathway. In addition, CA reduces oxidative stress by activating the Nrf2-mediated antioxidant response and suppresses inflammation and pyroptosis through inhibition of the NF-κB/NLRP3 signaling pathway, thereby protecting neuronal function and improving cognitive performance.