Ubiquitination of retinoic acid receptor alpha promotes severe acute pancreatitis-associated acute lung injury by releasing hexokinase 3 transcriptional repression

Lung macrophages constitute the first line of defense against environmental attack and participate in the pathogenesis of acute lung injury (ALI). In this study, we sought to elucidate the impact of HK3 on the regulation of macrophage phenotype in severe acute pancreatitis (SAP)-associated acute lung injury (PALI). HK3 expression was enhanced in lung macrophages of mice with SAP, and overexpression of HK3 in macrophages using adeno-associated viral vectors exacerbated PALI progression and increased macrophage M1 polarization in lung tissues. Overexpression of HK3 enhanced the glycolytic activity of macrophages, thereby polarizing macrophages toward the M1 phenotype. Retinoic acid receptor alpha (RARA) repressed HK3 transcription by binding to the promoter of HK3. Knockdown of HK3 inhibited the macrophage glycolysis induced by RARA knockdown and alleviated PALI development. NEDD4L mediated ubiquitination and degradation of RARA, and NEDD4L overexpression promoted macrophage glycolysis-induced increase in M1 polarization and inhibited M2 polarization. In peripheral blood CD14 + monocytes, NEDD4L and HK3 mRNA expression correlated positively with APACHE II scores and negatively with PaO₂/FiO₂, whereas RARA mRNA expression showed the opposite associations. In conclusion, NEDD4L-mediated degradation of RARA hinders its transcriptional repression of HK3 to activate macrophage glycolysis and M1 polarization in PALI development.