Clinical and translational medicine · 2026
Milk fat globule-EGF factor 8/ATP-binding cassette subfamily E member 1 axis maintains mitophagy flux homeostasis to suppress ferroptosis in acute pancreatitis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Ren Yifan, Lu Yuxuan, Cui Qing, Shang Hao, Fan Meng, Sun Yun, Shi Xiali, Wu Rongqian, Lu Hongwei
Аннотация
BACKGROUND: Acute pancreatitis (AP) is a severe inflammatory disorder in which mitochondrial dysfunction and ferroptosis critically drive acinar cell injury. Our previous work suggested a protective role for exogenous milk fat globule-epidermal growth factor 8 (MFG-E8) in AP. This study aimed to elucidate the molecular mechanism by which endogenous MFG-E8 mitigates mitochondrial damage and ferroptosis during AP.
METHODS: Two mouse models of AP were used for in vivo studies, while cerulein + lipopolysaccharide-induced mitophagy and ferroptosis in AR42J cells (cells of the rat exocrine pancreas) for in vitro studies. Mfge8 gene-defective mice and lentivirus were utilised to downregulate MFG-E8 expression in mice and overexpress MFG-E8 in cells, respectively. Dual gene modification was employed to overexpress MFG-E8 and simultaneously knockdown adenosine triphosphate (ATP)-binding 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.
RESULTS: Endogenous MFG-E8 expression was downregulated in experimental AP. Genetic deletion of Mfge8 aggravated mitochondrial ultrastructural damage, impaired mitophagy flux and intensified ferroptosis, as evidenced by increased lipid peroxidation, Fe2+ accumulation and depletion of glutathione peroxidase. Lentiviral overexpression of MFG-E8 in AR42J acinar cells restored mitophagy activity, preserved mitochondrial membrane potential and reduced oxidative stress. Mechanistically, co-immunoprecipitation confirmed that MFG-E8 directly interacts with ABCE1, a key mitophagy regulator. ABCE1 knockdown abolished the protective effects of MFG-E8 on mitochondrial function and ferroptosis suppression, indicating that the MFG-E8/ABCE1 axis is essential for maintaining mitophagy homeostasis. Pharmacological restoration of mitophagy or inhibition of ferroptosis rescued acinar cell injury caused by MFG-E8/ABCE1 dysregulation. In vivo, ferroptosis inhibition significantly improved pancreatic pathology and survival in Mfge8-deficient AP mice.
CONCLUSION: Endogenous MFG-E8 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.
KEY POINTS: Endogenous MFG-E8 is downregulated in acute pancreatitis (AP), disrupting MFG-E8/ABCE1 complex formation. MFG-E8/ABCE1 axis sustains Parkin-PINK1-mediated mitophagy to clear damaged mitochondria in pancreatic acinar cells. This axis suppresses ferroptosis by reducing Fe2+ accumulation and lipid peroxidation, alleviating AP-related pancreatic injury.
METHODS: Two mouse models of AP were used for in vivo studies, while cerulein + lipopolysaccharide-induced mitophagy and ferroptosis in AR42J cells (cells of the rat exocrine pancreas) for in vitro studies. Mfge8 gene-defective mice and lentivirus were utilised to downregulate MFG-E8 expression in mice and overexpress MFG-E8 in cells, respectively. Dual gene modification was employed to overexpress MFG-E8 and simultaneously knockdown adenosine triphosphate (ATP)-binding 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.
RESULTS: Endogenous MFG-E8 expression was downregulated in experimental AP. Genetic deletion of Mfge8 aggravated mitochondrial ultrastructural damage, impaired mitophagy flux and intensified ferroptosis, as evidenced by increased lipid peroxidation, Fe2+ accumulation and depletion of glutathione peroxidase. Lentiviral overexpression of MFG-E8 in AR42J acinar cells restored mitophagy activity, preserved mitochondrial membrane potential and reduced oxidative stress. Mechanistically, co-immunoprecipitation confirmed that MFG-E8 directly interacts with ABCE1, a key mitophagy regulator. ABCE1 knockdown abolished the protective effects of MFG-E8 on mitochondrial function and ferroptosis suppression, indicating that the MFG-E8/ABCE1 axis is essential for maintaining mitophagy homeostasis. Pharmacological restoration of mitophagy or inhibition of ferroptosis rescued acinar cell injury caused by MFG-E8/ABCE1 dysregulation. In vivo, ferroptosis inhibition significantly improved pancreatic pathology and survival in Mfge8-deficient AP mice.
CONCLUSION: Endogenous MFG-E8 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.
KEY POINTS: Endogenous MFG-E8 is downregulated in acute pancreatitis (AP), disrupting MFG-E8/ABCE1 complex formation. MFG-E8/ABCE1 axis sustains Parkin-PINK1-mediated mitophagy to clear damaged mitochondria in pancreatic acinar cells. This axis suppresses ferroptosis by reducing Fe2+ accumulation and lipid peroxidation, alleviating AP-related pancreatic injury.