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Our findings demonstrate that STAT3 inhibitors significantly enhance cell survival and reduce apoptosis in SH-SY5Y cells exposed to hydrogen peroxide. These protective effects are mediated through the ERK\/CREB signaling pathway rather than direct suppression of STAT3 phosphorylation. Further analysis revealed that the ERK pathway is a critical mediator of CREB activation following STAT3 inhibition. The protective effects of STAT3 inhibitors were significantly reduced in the presence of the ERK inhibitor PD98059, underscoring the importance of the ERK\/CREB axis in neuroprotection. We observed that STAT3 inhibitors promote CREB phosphorylation, leading to the upregulation of immediate early genes such as c-Fos, c-Jun, Arc, Egr-1, NR4A1, and Homer1a, as well as BDNF. These genes are crucial for synaptic plasticity and long-term memory formation, suggesting that STAT3 inhibition may ameliorate cognitive impairments in neurodegenerative conditions. Our results highlight the potential of STAT3 inhibitors to counteract oxidative stress and enhance cognitive functions by modulating the ERK\/CREB signaling pathway. 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