Glutathione peroxidase 3 preserves hepatocyte mitochondrial quality control to enhance macrophage pro-regenerative phenotype during liver regeneration

Abstract

Background: Precise regulation of mitochondrial function is critical for liver regeneration. However, the underlying regulatory mechanism remains elusive. Here, we aimed to investigate the role of hepatocellular glutathione peroxidase 3 (GPX3) in liver regeneration.

Methods: In a 70% partial hepatectomy (PH) mouse model, immunostaining and single-cell RNA sequencing revealed significant enrichment but down-regulation of mitochondrial oxidative phosphorylation pathways post-PH, along with up-regulated hypoxia-inducible factor 1a (HIF-1a) and GPX3 in hepatocytes. Single-cell analysis confirmed peak GPX3 expression in hepatocytes at day 2 post-PH. Hepatocyte-specific GPX3 knockout impaired mitochondrial function and delayed liver regeneration.

Results: Mechanistically, immunoprecipitation–mass spectrometry and MitoCarta3.0 analysis identified voltage-dependent anion channel 1 (VDAC1) as a direct GPX3-binding partner. GPX3 interacted with VDAC1 via its A2 domain (residues 75–150), suppressing VDAC1 oligomerisation to restore mitochondrial Ca²⁺ homeostasis and preserve mitochondrial quality control (MQC). Notably, GPX3 deficiency promoted mitochondrial DNA (mtDNA) release, activating the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway in macrophages. Persistent STING hyperactivation increased interferon production while suppressing hepatocyte growth factor release, further inhibiting regeneration. Critically, GPX3 overexpression enhanced liver regeneration in both PH and hepatic ischemia–reperfusion injury models, underscoring its central role across regenerative stressors.

Conclusions: In conclusion, GPX3 promotes liver regeneration by inhibiting VDAC1 oligomerisation to stabilise mitochondrial Ca²⁺ dynamics and MQC, while preventing mtDNA-mediated functional and phenotypic alterations in macrophages, positioning it as a therapeutic target for liver regeneration.

Key points:

Keywords

liver regeneration / hepatocyte / mitochondrial quality control / macrophage / cGAS-STING

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2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.