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Lactate dehydrogenase A mediated histone lactylation induced the pyroptosis through targeting HMGB1

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Abstract

Cerebral ischemia (CI), as the cerebrovascular disease with the highest incidence rate, is treated by limited intravenous thrombolysis and intravascular therapy to recanalize the embolized vessels. Recently, the discovery of histone lactylation proposes a potential molecular mechanism for the role of lactate in physiological and pathological processes. This study aimed to analyze the lactate dehydrogenase A (LDHA) mediated histone lactylation in CI reperfusion (CI/R) injury. Oxygen-glucose deprivation/reoxygenation (OGD/R) treated N2a cells and middle cerebral artery occlusion (MCAO) treated rats was used as the CI/R model in vivo and in vitro. Cell viability and pyroptosis was assessed using CCK-8 and flow cytometry. RT-qPCR was performed to detect the relative expression. The relationship between histone lactylation and HMGB1 was verified by CHIP assay. LDHA, HMGB1, lactate and histone lactylation was up-regulated in the OGD/R treated N2a cells. Additionally, LDHA knockdown decreased HMGB1 levels in vitro, and relieved CI/R injury in vivo. Besides, LDHA silencing declined the histone lactylation mark enrichment on HMGB1 promoter, and lactate supplement rescued it. What?s more, LDHA knockdown decreased the IL-18 and IL-1β contents, and the cleaved-caspase-1 and GSDMD-N protein levels in the OGD/R treated N2a cells, which was reversed by HMGB1 overexpression. Knockdown of LDHA suppressed the pyroptosis in the N2a cells induced by OGD/R, which was reversed by HMGB1 overexpression. Mechanistically, LDHA mediated the histone lactylation induced pyroptosis through targeting HMGB1 in the CI/R injury.

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Data Availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Nangang District, Harbin City, 150001, Heilongjiang Province, China

    Xuan Yao

  2. The Second Department of Operating Room, The Second Affiliated Hospital of Harbin Medical University, Nangang District, Harbin City, 150001, Heilongjiang Province, China

    Chao Li

  3. The Key Laboratory of Anesthesiology and lntensive Care Research of Heilongjiang Province, Harbin, China

    Xuan Yao

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Contributions

All authors participated in the design, interpretation of the studies and analysis of the data and review of the manuscript. X Y drafted the work and revised it critically for important intellectual content and made substantial contributions to the conception or design of the work; C L was responsible for the acquisition, analysis, or interpretation of data for the work.

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Correspondence to Xuan Yao.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of The Second Affiliated Hospital of Harbin Medical University.

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Yao, X., Li, C. Lactate dehydrogenase A mediated histone lactylation induced the pyroptosis through targeting HMGB1. Metab Brain Dis 38, 1543–1553 (2023). https://doi.org/10.1007/s11011-023-01195-6

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