OXCT1-induced Succinylation at K81 Shields HADH from HSPA8-Mediated Degradation in alveolar epithelial cells to Attenuate Lung Ischemia-Reperfusion Injury.

Lung transplantation serves as a life-saving therapeutic intervention for patients with end-stage pulmonary diseases, with the lung ischemia-reperfusion injury (LIRI) as the major challenge. Correcting lipid metabolic dysregulation in alveolar epithelial cells by targeting key causative molecules is a promising therapeutic strategy for LIRI. Quantitative proteomics and metabolomics revealed that dysregulated fatty acid metabolism dominates the LIRI metabolic network. Transcriptome analysis of human LIRI samples indicated disorder of fatty acid oxidation and mitochondrial homeostasis disruption. Within this pathway, hydroxyacyl-CoA dehydrogenase (HADH), a key mitochondrial β-oxidation enzyme, was identified as a potential biomarker (AUC = 0.79). In Sprague-Dawley (SD) rats exposed to 60-min ischemia and 2-h reperfusion (I/R), the pulmonary expression of HADH decreased by about 50%. HADH overexpression mediated by adenoviruses conferred multi-faceted pulmonary protection both in vivo and in vitro: in I/R-subjected SD rats, it alleviated mitochondrial impairment, boosted ATP production, diminished ROS levels, and limited alveolar apoptosis; these effects were corroborated in RLE-6TN AT2 cells exposed to 2-h hypoxia/4-h reoxygenation (H/R). Building on evidence that lysine succinylation modulates mitochondrial enzyme activity, we further identified 7 succinylated lysine residues within the catalytic domain of HADH-rather than its dimerization domain-highlighting its potential functional significance. Specifically, 3-oxoacid CoA-transferase 1 (OXCT1) increased HADH succinylation at lysine 81 (K81), stabilizing HADH by blocking its degradation via chaperone-mediated autophagy (CMA). The activated OXCT1-HADH axis reduced non-esterified fatty acid accumulation. OXCT1-succinylated K81 disrupted binding between HADH and heat shock protein A8 (HSPA8), a CMA recognition factor. HADH has a canonical HSPA8-binding CMA motif; mutating its key glutamine (Q132) or silencing HSPA8 inhibited CMA-mediated HADH degradation. Virtual screening shows that small-molecule drugs binding to HSPA8's active pocket (near its interaction region with HADH K81) have potential in treating post-lung transplantation dysfunction. Our findings elucidate the succinylation-dependent regulatory mechanism of HADH and provide a potential therapeutic strategy for LIRI.

• Publication year

  2026

• Venue

  Free Radical Biology & Medicine

• Publication date

  2026-02-01

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1016/j.freeradbiomed.2026.02.072PMID 41771361
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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