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Войти в исследования Brain research bulletin · 2025
HDAC2 exacerbates carbon monoxide poisoning-induced brain injury by promoting neuronal ferroptosis through the NEDD4L/ACSL4 axis.
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Liu Zuolong, Bian Miao, He Jingjing, Pang Li
Аннотация
BACKGROUND: Acute carbon monoxide poisoning (ACMP) induces neuronal damage and ferroptosis, but the role of histone deacetylase 2 (HDAC2) in this process remains unclear.
METHODS: Male C57BL/6 mice were exposed to CO to establish ACMP models and treated with the HDAC2 inhibitor santacruzamate A (STA). Cognitive deficits were evaluated using Morris water maze, while neuronal injury was assessed through hematoxylin-eosin and Nissl staining. Ferroptosis was analyzed using commercial kits for glutathione (GSH), malondialdehyde (MDA), and Fe²⁺, combined with Western blot for glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), and solute carrier family 7 member 11 (SLC7A11). In HT22 neurons subjected to oxygen-glucose deprivation/reperfusion (OGD/R), mechanistic studies were performed by transfecting sh-HDAC2, oe-NEDD4L, or sh-NEDD4L to investigate HDAC2-mediated regulation of the NEDD4L/ACSL4 axis. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) was used to examine histone H3 lysine 27 acetylation (H3K27ac) binding to the NEDD4L promoter. NEDD4L-ACSL4 interactions and ACSL4 ubiquitination were detected by co-immunoprecipitation (Co-IP)/Western blot.
RESULTS: ACMP mice showed prolonged escape latency, increased neuronal necrosis, and upregulated HDAC2 expression. STA treatment attenuated cognitive deficits, reduced neuronal damage, and inhibited ferroptosis. In vitro, HDAC2 knockdown increased H3K27ac at the NEDD4L promoter, thereby enhancing NEDD4L expression. NEDD4L overexpression subsequently promoted ACSL4 ubiquitination and degradation. Co-knockdown of HDAC2 and NEDD4L abrogated the protective effects of HDAC2 inhibition, resulting ferroptosis and cell injury.
CONCLUSION: HDAC2 exacerbates ACMP-induced ferroptosis and neuronal injury by repressing NEDD4L via H3K27 deacetylation, thereby reducing ACSL4 ubiquitination and degradation.
METHODS: Male C57BL/6 mice were exposed to CO to establish ACMP models and treated with the HDAC2 inhibitor santacruzamate A (STA). Cognitive deficits were evaluated using Morris water maze, while neuronal injury was assessed through hematoxylin-eosin and Nissl staining. Ferroptosis was analyzed using commercial kits for glutathione (GSH), malondialdehyde (MDA), and Fe²⁺, combined with Western blot for glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), and solute carrier family 7 member 11 (SLC7A11). In HT22 neurons subjected to oxygen-glucose deprivation/reperfusion (OGD/R), mechanistic studies were performed by transfecting sh-HDAC2, oe-NEDD4L, or sh-NEDD4L to investigate HDAC2-mediated regulation of the NEDD4L/ACSL4 axis. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) was used to examine histone H3 lysine 27 acetylation (H3K27ac) binding to the NEDD4L promoter. NEDD4L-ACSL4 interactions and ACSL4 ubiquitination were detected by co-immunoprecipitation (Co-IP)/Western blot.
RESULTS: ACMP mice showed prolonged escape latency, increased neuronal necrosis, and upregulated HDAC2 expression. STA treatment attenuated cognitive deficits, reduced neuronal damage, and inhibited ferroptosis. In vitro, HDAC2 knockdown increased H3K27ac at the NEDD4L promoter, thereby enhancing NEDD4L expression. NEDD4L overexpression subsequently promoted ACSL4 ubiquitination and degradation. Co-knockdown of HDAC2 and NEDD4L abrogated the protective effects of HDAC2 inhibition, resulting ferroptosis and cell injury.
CONCLUSION: HDAC2 exacerbates ACMP-induced ferroptosis and neuronal injury by repressing NEDD4L via H3K27 deacetylation, thereby reducing ACSL4 ubiquitination and degradation.