Gm26550 Modulates Learning and Memory by Increasing IGF1 mRNA Expression and Stability in Nrf2^-/- Mice

Nrf2 dysfunction is implicated in learning and memory deficits, but the involvement of non-coding RNAs in Nrf2-dependent cognitive regulation remains largely unexplored. Here, by analyzing the expression profiles of lncRNAs and mRNAs in the hippocampus of wild-type (WT) and Nrf2 knockout (Nrf2^-/-) mice, we identified a decreased expression of lncRNA Gm26550 in Nrf2^-/- mice. Overexpression of Gm26550 enhances hippocampal neuronal synaptic plasticity and rescues learning and memory deficits in Nrf2^-/- mice. Mechanistically, Nrf2 directly binds the promoter of Gm26550 to drive its transcriptional activation and upregulate its expression. Gm26550 elevates IGF1 abundance via two regulatory pathways to maintain cognitive function: first, it functionally counteracts miR-26a-5p-mediated repression of IGF1; second, it interacts with the KH3/KH4 domain of KHSRP to block KHSRP-triggered degradation of IGF1 mRNA. Collectively, our results reveal that Gm26550 maintains IGF1 expression and transcript stability through miR-dependent antagonism and RBP sequestration, thereby governing learning and memory downstream of Nrf2. This work expands the understanding of the downstream molecular network controlled by Nrf2.