Tissue & cell · 2026
TET1-mediated demethylation of UGT1A1 suppresses neuronal ferroptosis and brain injury in bilirubin encephalopathy.
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Yang Xiaoling, Duan Qingmingai, Lei Beibei, Yan Jun
Аннотация
BACKGROUND: Bilirubin encephalopathy (BE) is a severe neurological complication of neonatal hyperbilirubinemia, but the molecular mechanisms underlying bilirubin-induced brain injury remain unclear. We investigated whether UDP-glucuronosyltransferase 1A1 (UGT1A1) regulates neuronal ferroptosis in BE and whether this process is controlled by ten-eleven translocation methylcytosine dioxygenase 1 (TET1)-mediated demethylation.
METHODS: BE rat models were established by cisterna magna bilirubin injection, and bilirubin-treated PC12 cells were used for in vitro analysis. UGT1A1 and TET1 were overexpressed in vivo and in vitro, and UGT1A1 knockdown, Erastin, and 5-aza-2'-deoxycytidine were used for mechanistic studies. Brain injury, neurological function, ferroptosis-related oxidative stress, apoptosis, inflammatory factors, promoter methylation, and protein expression were evaluated by biochemical assays, Morris water maze, histology, TUNEL staining, qRT-PCR, western blotting, and chromatin immunoprecipitation (ChIP).
RESULTS: UGT1A1 was downregulated in BE models. UGT1A1 overexpression reduced bilirubin accumulation, brain edema, neuronal injury, and cognitive impairment in BE rats, and suppressed ferroptosis by decreasing iron, malondialdehyde, acyl-CoA synthetase long-chain family member 4 (ACSL4), apoptosis, and inflammatory factors while restoring antioxidant indices and glutathione peroxidase 4 (GPX4). In bilirubin-treated PC12 cells, UGT1A1 also alleviated ferroptosis-related injury, whereas Erastin weakened these protective effects. UGT1A1 promoter methylation was increased in BE model cells, while TET1 expression was reduced in hippocampal tissue. TET1 bound the UGT1A1 promoter, reduced its methylation, restored UGT1A1 expression, and alleviated ferroptosis. UGT1A1 knockdown weakened the protective effects of TET1 in neuronal cells.
CONCLUSION: TET1-mediated demethylation of UGT1A1 suppresses neuronal ferroptosis and brain injury in BE, identifying the TET1/UGT1A1 axis as a potential therapeutic target.
METHODS: BE rat models were established by cisterna magna bilirubin injection, and bilirubin-treated PC12 cells were used for in vitro analysis. UGT1A1 and TET1 were overexpressed in vivo and in vitro, and UGT1A1 knockdown, Erastin, and 5-aza-2'-deoxycytidine were used for mechanistic studies. Brain injury, neurological function, ferroptosis-related oxidative stress, apoptosis, inflammatory factors, promoter methylation, and protein expression were evaluated by biochemical assays, Morris water maze, histology, TUNEL staining, qRT-PCR, western blotting, and chromatin immunoprecipitation (ChIP).
RESULTS: UGT1A1 was downregulated in BE models. UGT1A1 overexpression reduced bilirubin accumulation, brain edema, neuronal injury, and cognitive impairment in BE rats, and suppressed ferroptosis by decreasing iron, malondialdehyde, acyl-CoA synthetase long-chain family member 4 (ACSL4), apoptosis, and inflammatory factors while restoring antioxidant indices and glutathione peroxidase 4 (GPX4). In bilirubin-treated PC12 cells, UGT1A1 also alleviated ferroptosis-related injury, whereas Erastin weakened these protective effects. UGT1A1 promoter methylation was increased in BE model cells, while TET1 expression was reduced in hippocampal tissue. TET1 bound the UGT1A1 promoter, reduced its methylation, restored UGT1A1 expression, and alleviated ferroptosis. UGT1A1 knockdown weakened the protective effects of TET1 in neuronal cells.
CONCLUSION: TET1-mediated demethylation of UGT1A1 suppresses neuronal ferroptosis and brain injury in BE, identifying the TET1/UGT1A1 axis as a potential therapeutic target.