Pancreas · 2026
OGT-Mediated O-GlcNAcylation of ATF3 Transcriptionally Activates ACSL1 to Aggravate Ferroptosis in Severe Acute Pancreatitis: ATF3 O-GlcNAcylation Promotes SAP Ferroptosis.
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Weng Xi, Luo Junjie, Xu Jie, Huang Shuo, Hu Juntao, Tang Zhanhong
Аннотация
BACKGROUND: Acute pancreatitis (AP) is a common cause of acute abdominal pain, and about 25% of AP patients will develop severe acute pancreatitis (SAP), causing damage to multiple organ functions and eventually death. Ferroptosis has recently been identified as significantly contributing to SAP progression. Our study aims to elucidate a novel mechanism of ferroptosis in which O-GlcNAcylation of ATF3 regulates in the context of SAP.
METHODS: AR42J cells were treated with L-Arginine to induce SAP cell model. Levels of GSH, MDA, LPO, Fe 2+ , and LDH were measured by their commercial kits. The Fura-3 AM probes and C11 BODIPY 581/591 probe were used to detect Ca 2+ levels or lipid ROS. To demonstrate the regulatory relationship between ATF3 and ACSL1, ChIP and dual-luciferase reporter assays were applied. Co-IP and sWGA pull-down assays were conducted to verify the O-GlcNAcylation level. The co-localization of OGT and ATF3 was displayed by immunofluorescence. Male SD rats were intraperitoneally injected with L-Arginine to establish a SAP model. Pancreatic histopathologic alterations were subsequently evaluated by HE staining.
RESULTS: Ferroptosis and ATF3 increased by treating L-Arginine in AR42J cells. ATF3 knockdown suppressed MDA, LPO, Fe 2+ , and lipid ROS levels but improved GSH and cell viability. OGT was elevated in SAP, and it promoted the O-GlcNAcylation of ATF3, resulting in the aggravation of ferroptosis. Both OGT inhibitor and OGT knockdown limited O-GlcNAcylation, ATF3, and ACSL1 levels. ATF3 directly bound to the promoter region of ACSL1 to upregulate its expression. ACSL1 overexpression abolished the suppression of ferroptosis in AR42J cells caused by ATF3 reduction. Inhibiting the ATF3 O-GlcNAcylation suppresses ferroptosis and attenuates pancreatic tissue injury in SAP rat.
CONCLUSIONS: The OGT-mediated O-GlcNAcylation of ATF3 is significantly enhanced, thereby promoting the transcriptional activity of ASCL1 and exacerbating ferroptosis in SAP.
METHODS: AR42J cells were treated with L-Arginine to induce SAP cell model. Levels of GSH, MDA, LPO, Fe 2+ , and LDH were measured by their commercial kits. The Fura-3 AM probes and C11 BODIPY 581/591 probe were used to detect Ca 2+ levels or lipid ROS. To demonstrate the regulatory relationship between ATF3 and ACSL1, ChIP and dual-luciferase reporter assays were applied. Co-IP and sWGA pull-down assays were conducted to verify the O-GlcNAcylation level. The co-localization of OGT and ATF3 was displayed by immunofluorescence. Male SD rats were intraperitoneally injected with L-Arginine to establish a SAP model. Pancreatic histopathologic alterations were subsequently evaluated by HE staining.
RESULTS: Ferroptosis and ATF3 increased by treating L-Arginine in AR42J cells. ATF3 knockdown suppressed MDA, LPO, Fe 2+ , and lipid ROS levels but improved GSH and cell viability. OGT was elevated in SAP, and it promoted the O-GlcNAcylation of ATF3, resulting in the aggravation of ferroptosis. Both OGT inhibitor and OGT knockdown limited O-GlcNAcylation, ATF3, and ACSL1 levels. ATF3 directly bound to the promoter region of ACSL1 to upregulate its expression. ACSL1 overexpression abolished the suppression of ferroptosis in AR42J cells caused by ATF3 reduction. Inhibiting the ATF3 O-GlcNAcylation suppresses ferroptosis and attenuates pancreatic tissue injury in SAP rat.
CONCLUSIONS: The OGT-mediated O-GlcNAcylation of ATF3 is significantly enhanced, thereby promoting the transcriptional activity of ASCL1 and exacerbating ferroptosis in SAP.