Hexokinase 2 deficiency protects against sepsis-associated lung injury via suppressing the NF-κB signaling pathway

Inflammation plays a pivotal role in the pathogenesis and treatment of sepsis-associated lung injury (S-ALI). Although hexokinase 2 (HK2) is known to be involved in regulating inflammation, metabolism, and mitochondrial homeostasis, its mechanism in S-ALI remains unclear.

In the cecal ligation and puncture (CLP)-induced S-ALI mouse model, haploinsufficiency of HK2 or pharmacological inhibition of HK2 by Lonidamine (LND) was administered. The effects of gene silencing or pharmacological inhibition of HK2 on pulmonary inflammation, lipid metabolism and mitochondrial damage were evaluated using qRT-PCR, immunofluorescence, Western blotting and transmission electron microscopy. Furthermore, siRNA and LND were used to further investigate the impact of gene silencing or pharmacological inhibition of HK2 on the NF-κB signaling pathway in MH-S cells.

HK2 expression was elevated in lung tissues of CLP-induced septic mice. HK2 haploinsufficiency attenuated CLP-induced lung injury by suppressing M1 polarization of pulmonary macrophages, thereby exerting a lung-protective effect. HK2 haploinsufficiency also improved lipid metabolism, mitigated mitochondrial damage, and reduced endoplasmic reticulum stress in S-ALI. Genetic silencing or pharmacological inhibition of HK2 in LPS-stimulated MH-S alveolar macrophages modulated IκBα expression and suppressed nuclear NF-κB.

HK2 partial antagonism ameliorated CLP-induced pulmonary inflammation, lipid metabolic dysfunction, and mitochondrial damage, potentially through modulation of the NF-κB signaling pathway.