European journal of pharmacology · 2026
Sirtuin 1 deacetylates NCOA4 to suppress ferritinophagy-mediated ferroptosis and ameliorate acute pancreatitis.
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Shen Zhao-Jian, Han Zi-Yu, Fu Lu, Ma Shi-Ya, Lu Zhong-Hua, Sun Yun, Yu Wei-Li
Аннотация
BACKGROUND: Acute pancreatitis (AP) is a severe inflammatory disease lacking mechanism-based therapy. Ferroptosis driven by Nuclear receptor coactivator (NCOA4)-mediated ferritinophagy contributes to acinar cell injury, but how NCOA4 is regulated post-translationally in AP remains unknown. We examined whether Sirtuin 1 (SIRT1) deacetylates NCOA4 to suppress ferritinophagy-dependent ferroptosis.
METHODS: Serum SIRT1, NCOA4 and inflammatory cytokines were measured in AP patients and healthy controls. In vivo, AP was induced in rats by L-arginine, with or without resveratrol (SIRT1 activator) or EX527 (SIRT1 inhibitor). In vitro, AR42J cells were transfected with SIRT1/NCOA4 plasmids or siRNAs before caerulein treatment. Ferroptosis markers, protein interactions, and clinical correlations were assessed.
RESULTS: In AP patients, serum SIRT1 correlated negatively with disease severity and NCOA4, while NCOA4 correlated positively with disease severity and inflammatory cytokines. In AP rat model, SIRT1 activation via resveratrol lowered NCOA4, increased Ferritin heavy chain 1 (FTH1), reduced lipid peroxidation and pancreatic injury, whereas SIRT1 inhibition had opposite effects. In in vitro AP model, SIRT1 overexpression produced similar protection. NCOA4 overexpression induced ferritinophagy (LC3 II accumulation, FTH1 decline) and ferroptosis. Co-expressing NCOA4 together with SIRT1 counteracted the protection afforded by SIRT1 alone. Co-immunoprecipitation confirmed a direct SIRT1-NCOA4 interaction. SIRT1 overexpression decreased NCOA4 acetylation and expression. SIRT1 knockdown increased both.
CONCLUSIONS: Serum SIRT1 and NCOA4 may serve as predictive markers for AP severity. SIRT1 deacetylates NCOA4, down-regulates it, and thereby suppresses ferritinophagy-dependent ferroptosis, protecting against AP. Resveratrol exerts a protective effect against AP by inhibiting ferroptosis dependent on ferritinophagy through activating SIRT1 to deacetylate NCOA4.
METHODS: Serum SIRT1, NCOA4 and inflammatory cytokines were measured in AP patients and healthy controls. In vivo, AP was induced in rats by L-arginine, with or without resveratrol (SIRT1 activator) or EX527 (SIRT1 inhibitor). In vitro, AR42J cells were transfected with SIRT1/NCOA4 plasmids or siRNAs before caerulein treatment. Ferroptosis markers, protein interactions, and clinical correlations were assessed.
RESULTS: In AP patients, serum SIRT1 correlated negatively with disease severity and NCOA4, while NCOA4 correlated positively with disease severity and inflammatory cytokines. In AP rat model, SIRT1 activation via resveratrol lowered NCOA4, increased Ferritin heavy chain 1 (FTH1), reduced lipid peroxidation and pancreatic injury, whereas SIRT1 inhibition had opposite effects. In in vitro AP model, SIRT1 overexpression produced similar protection. NCOA4 overexpression induced ferritinophagy (LC3 II accumulation, FTH1 decline) and ferroptosis. Co-expressing NCOA4 together with SIRT1 counteracted the protection afforded by SIRT1 alone. Co-immunoprecipitation confirmed a direct SIRT1-NCOA4 interaction. SIRT1 overexpression decreased NCOA4 acetylation and expression. SIRT1 knockdown increased both.
CONCLUSIONS: Serum SIRT1 and NCOA4 may serve as predictive markers for AP severity. SIRT1 deacetylates NCOA4, down-regulates it, and thereby suppresses ferritinophagy-dependent ferroptosis, protecting against AP. Resveratrol exerts a protective effect against AP by inhibiting ferroptosis dependent on ferritinophagy through activating SIRT1 to deacetylate NCOA4.