Targeted degradation of hexokinase 2 for anti‑inflammatory treatment in acute lung injury

Abstract

Acute lung injury (ALI) is an acute inflammatory lung disease associated with both innate and adaptive immune responses. Hexokinase 2 (HK2) is specifically highly expressed in numerous types of inflammation-related diseases and models. In the present study in vitro and in vivo effects of targeted degradation of HK2 on ALI were explored. The degradation of HK2 by the targeting peptide TAT (transactivator of transcription protein of HIV-1)-ataxin 1 (ATXN1)-chaperone-mediated autophagy-targeting motif (CTM) was demonstrated by ELISA and western blotting in vitro and in vivo . The inhibitory effects of TAT-ATXN1-CTM on lipopolysaccharide (LPS)-induced inflammatory responses were examined using ELISAs. The therapeutic effects of TAT-ATXN1-CTM on LPS-induced ALI were examined via histological examination and ELISAs in mice. 10 µM TAT-ATXN1-CTM administration decreased HK2 protein expression and the secretion of proinflammatory cytokines (TNF-α and IL-1β) without altering HK2 mRNA expression in LPS-treated both in vitro and in vivo , while pathological lung tissue damage and the accumulation of leukocytes, neutrophils, macrophages and lymphocytes in ALI were also significantly suppressed by 10 µM TAT-ATXN1-CTM treatment. TAT-ATXN1-CTM exhibited anti-inflammatory activity in vitro and decreased the severity of ALI in vivo . HK2 degradation may represent a novel therapeutic approach for ALI.