Abstract

Abstract Objectives This study explored the mechanism of FTO in regulating neuron apoptosis in hypoxic-ischemic brain damage (HIBD) models via PDCD5. Methods Neonatal SD rats were treated by unilateral common carotid artery ligation to establish HIBD model, while primary hippocampal neurons were induced by oxygen-glucose deprivation (OGD) to mimic the in vitro model. The expression levels of FTO and PDCD5 mRNA and proteins were assessed by qRT-PCR and Western blot, respectively. Cell apoptosis was evaluated by CCK-8 assay and flow cytometry. Furthermore, cerebral infarct area and neuronal damage in HIBD rats were determined by TTC and Nissl stainings, whereas apoptosis in brain tissue was examined by TUNEL staining. MeRIP assay was performed to detect the levels of m6A modification, and RIP assay to confirm their binding relationship. Results HIBD rats had decreased FTO expression and elevated PDCD5 expression, accompanied by increased cerebral infarction and apoptosis. Overexpression of FTO inhibited neuronal apoptosis and alleviated HIBD progression. Additionally, knockdown of PDCD5 suppressed OGD-induced neuronal apoptosis in OGD-induced primary hippocampal neurons, while such effect was nullified by overexpression of FTO. FTO interacted with PDCD5 to influence the m6A modification level of PTBP1 and subsequently decrease its mRNA stability. Conclusions Down-regulation of FTO expression in HIBD reduces the degradation of M6A-modified PDCD5 mRNA, thereby increasing PDCD5 protein expression. This elevation in PDCD5 promotes neuronal apoptosis, which exacerbates the progression of HIBD.