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However, the underlying regulatory mechanism remains elusive. Here, we aimed to investigate the role of hepatocellular glutathione peroxidase 3 (GPX3) in liver regeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In a 70% partial hepatectomy (PH) mouse model, immunostaining and single\u2010cell RNA sequencing revealed significant enrichment but down\u2010regulation of mitochondrial oxidative phosphorylation pathways post\u2010PH, along with up\u2010regulated hypoxia\u2010inducible factor 1a (HIF\u20101a) and GPX3 in hepatocytes. Single\u2010cell analysis confirmed peak GPX3 expression in hepatocytes at day 2 post\u2010PH. Hepatocyte\u2010specific GPX3 knockout impaired mitochondrial function and delayed liver regeneration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Mechanistically, immunoprecipitation\u2013mass spectrometry and MitoCarta3.0 analysis identified voltage\u2010dependent anion channel 1 (VDAC1) as a direct GPX3\u2010binding partner. GPX3 interacted with VDAC1 via its A2 domain (residues 75\u2013150), suppressing VDAC1 oligomerisation to restore mitochondrial Ca\n                      <jats:sup>2+<\/jats:sup>\n                      homeostasis and preserve mitochondrial quality control (MQC). Notably, GPX3 deficiency promoted mitochondrial DNA (mtDNA) release, activating the cyclic GMP\u2013AMP synthase (cGAS)\u2013stimulator 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\u2013reperfusion injury models, underscoring its central role across regenerative stressors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      In conclusion, GPX3 promotes liver regeneration by inhibiting VDAC1 oligomerisation to stabilise mitochondrial Ca\n                      <jats:sup>2+<\/jats:sup>\n                      dynamics and MQC, while preventing mtDNA\u2010mediated functional and phenotypic alterations in macrophages, positioning it as a therapeutic target for liver regeneration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            GPX3 directly binds VDAC1 via its A2 domain to suppress VDAC1 oligomerisation, restoring mitochondrial Ca\n                            <jats:sup>2<\/jats:sup>\n                            <jats:sup>+<\/jats:sup>\n                            homeostasis and preserving mitochondrial quality control during liver regeneration.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>GPX3 deficiency promotes mtDNA release, hyperactivating the cGAS\u2013STING pathway in macrophages and suppressing hepatocyte growth factor (HGF) release.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>GPX3 overexpression enhances liver regeneration in both partial hepatectomy and hepatic ischemia\u2013reperfusion injury models, highlighting its therapeutic potential.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70695","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T06:43:52Z","timestamp":1780123432000},"source":"Crossref","is-referenced-by-count":1,"title":["Glutathione peroxidase 3 preserves hepatocyte mitochondrial quality control to enhance macrophage pro\u2010regenerative phenotype during liver regeneration"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2068-2528","authenticated-orcid":false,"given":"Yuechen","family":"Wang","sequence":"first","affiliation":[{"name":"Hepatobiliary Center, The First Affiliated Hospital with Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Key Laboratory of Hepatobiliary Tumors, National Health Commission, 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