Lysine demethylase 1A alleviates Alzheimer disease progression by regulating the leucine carboxyl methyltransferase 1/protein phosphatase 2 catalytic subunit alpha/transcription factor EB pathway via O‐GlcNAcase‐mediated forkhead box transcription factor A2 O‐GlcNAcylation modification

Background and Purpose Lysine demethylase 1A (KDM1A; LSD1) plays anti‐ferroptosis role and has been confirmed to be lowly expressed in Alzheimer disease (AD). This study explores whether LSD1 affects the progression of AD by regulating ferroptosis and related mechanisms involved. Experimental Approach AD mice (APP/PS1 double transgenic) were injected with adeno‐associated virus expressing LSD1 overexpression vector, or siRNA against leucine carboxyl methyltransferase 1 (LCMT1)/transcription factor EB (TFEB). SH‐SY5Y cells were treated with Aβ1‐42 to establish an AD cell injury model. The levels of lipid peroxidation and ferroptosis‐related markers were tested to evaluate ferroptosis. The protein levels of LSD1, O‐GlcNAcase (OGA), forkhead box transcription factor A2 (FOXA2), LCMT1, protein phosphatase 2A catalytic subunit alpha (PP2A) and TFEB were detected by western blot. The mRNA levels of LSD1 and OGA were assessed using quantitative real‐time PCR. Interactions between targets were measured by ChIP‐qPCR, DNA pull down, co‐immunoprecipitation and dual‐luciferase reporter assay. Key Results LSD1 upregulation suppressed neuronal ferroptosis to attenuate AD progression in mice. Further, LSD1 overexpression alleviated Aβ1‐42‐induced cell injury by reducing OGA transcription and expression. OGA inhibited FOXA2 O‐GlcNAcylation modification to promote its expression and transcriptional activity. Also, FOXA2 repressed LCMT1‐mediated the activation of PP2A and TFEB. Furthermore, LSD1 alleviated AD process by inhibiting neuronal ferroptosis through the regulation of OGA/FOXA2/LCMT1/PP2A/TFEB axis. Conclusions and Implications Overall, LSD1 restrained neuronal ferroptosis to alleviate the progression of AD by regulating LCMT1/PP2A/TFEB pathway via OGA‐mediated FOXA2 O‐GlcNAcylation modification, providing novel mechanistic insights into the deeper understanding of AD pathogenesis and the development of potential drug targets.