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Our previous work suggested a protective role for exogenous milk fat globule\u2014epidermal growth factor 8 (MFG\u2010E8) in AP. This study aimed to elucidate the molecular mechanism by which endogenous MFG\u2010E8 mitigates mitochondrial damage and ferroptosis during AP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Two mouse models of AP were used for in vivo studies, while cerulein + lipopolysaccharide\u2010induced mitophagy and ferroptosis in AR42J cells (cells of the rat exocrine pancreas) for in vitro studies.\n                      <jats:italic>Mfge8<\/jats:italic>\n                      gene\u2010defective mice and lentivirus were utilised to downregulate MFG\u2010E8 expression in mice and overexpress MFG\u2010E8 in cells, respectively. Dual gene modification was employed to overexpress MFG\u2010E8 and simultaneously knockdown adenosine triphosphate (ATP)\u2010binding cassette subfamily E member 1 (ABCE1) in vitro. One mitophagy agonist and two ferroptosis inhibitors were used in both in vitro and in vivo experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Endogenous MFG\u2010E8 expression was downregulated in experimental AP. Genetic deletion of\n                      <jats:italic>Mfge8<\/jats:italic>\n                      aggravated mitochondrial ultrastructural damage, impaired mitophagy flux and intensified ferroptosis, as evidenced by increased lipid peroxidation, Fe\n                      <jats:sup>2+<\/jats:sup>\n                      accumulation and depletion of glutathione peroxidase. Lentiviral overexpression of MFG\u2010E8 in AR42J acinar cells restored mitophagy activity, preserved mitochondrial membrane potential and reduced oxidative stress. Mechanistically, co\u2010immunoprecipitation confirmed that MFG\u2010E8 directly interacts with ABCE1, a key mitophagy regulator. ABCE1 knockdown abolished the protective effects of MFG\u2010E8 on mitochondrial function and ferroptosis suppression, indicating that the MFG\u2010E8\/ABCE1 axis is essential for maintaining mitophagy homeostasis. Pharmacological restoration of mitophagy or inhibition of ferroptosis rescued acinar cell injury caused by MFG\u2010E8\/ABCE1 dysregulation. In vivo, ferroptosis inhibition significantly improved pancreatic pathology and survival in\n                      <jats:italic>Mfge8<\/jats:italic>\n                      \u2010deficient AP mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Endogenous MFG\u2010E8 protects against AP by binding ABCE1 to sustain mitophagy flux and inhibit ferroptosis. Targeting this axis offers a promising therapeutic strategy for mitigating pancreatic injury.<\/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>Endogenous MFG\u2010E8 is downregulated in acute pancreatitis (AP), disrupting MFG\u2010E8\/ABCE1 complex formation.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>MFG\u2010E8\/ABCE1 axis sustains Parkin\u2010PINK1\u2010mediated mitophagy to clear damaged mitochondria in pancreatic acinar cells.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            This axis suppresses ferroptosis by reducing Fe\n                            <jats:sup>2+<\/jats:sup>\n                            accumulation and lipid peroxidation, alleviating AP\u2010related pancreatic injury.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70619","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T09:22:52Z","timestamp":1771406572000},"source":"Crossref","is-referenced-by-count":2,"title":["Milk fat globule\u2014EGF factor 8\/ATP\u2010binding cassette subfamily E member 1 axis maintains mitophagy flux homeostasis to suppress ferroptosis in acute pancreatitis"],"prefix":"10.1002","volume":"16","author":[{"given":"Yifan","family":"Ren","sequence":"first","affiliation":[{"name":"Department of General Surgery The Second Affiliated Hospital of Xi'an Jiaotong University  Xi'an China"},{"name":"National Local Joint Engineering Research Center for 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