| Accession |
PRJCA022629 |
| Title |
FTO-deficiency in aged livers exacerbates ferroptosis during ischaemia/reperfusion injury via upregulating of ACSL4 and TFRC |
| Relevance |
Medical |
| Data types |
Epigenomics
MassSpectrometry，CLIP-seq
|
| Organisms |
Mus musculus
Homo sapiens
|
| Description |
Aged livers are more prone to hepatic ischaemia/reperfusion injury (HIRI), which severely limits their utilization in liver transplantation (LT); however, the potential mechanism is complicated and remains unclear. Ferroptosis was previously shown to be critical for the pathogenesis of age-related diseases. Whether ferroptosis also contributes to aged HIRI is unknown. We used clinical donor liver specimens collected at pre- and postreperfusion, a murine model of aged HIRI, and mouse primary and human hepatocytes to examine the role of ferroptosis in aged HIRI. Mass spectrometry, methylate RNA immunoprecipitation sequencing (MeRIP-seq) and adeno-associated virus (AAV)-8 were used to identify and validate the potential regulatory mechanism. Aged livers are indeed more susceptible to HIRI and exhibit a higher degree of ferroptosis. Inhibiting ferroptosis obviously attenuated aged HIRI. Mass spectrometry revealed that fat mass and obesity-associated gene (FTO), a pivotal m6A demethylase, was downregulated in aged livers, especially during IRI. Series of in vivo and in vitro assays demonstrated FTO ameliorated aged HIRI by inhibiting ferroptosis. MeRIP-seq showed acyl-CoA synthetase long chain family 4 (ACSL4) and transferrin receptor protein 1 (TFRC), two key inducers of ferroptosis, were targets of FTO. The mitigating effect of FTO on aged HIRI required the inhibition of ACSL4 and TFRC mRNA stability in a m6A-dependent manner. Furthermore, we demonstrated NAD+ precursor nicotinamide mononucleotide (NMN) could upregulate FTO demethylase activity to suppress ferroptosis and attenuate aged HIRI. |
| Sample scope |
Multispecies |
| Release date |
2024-04-08 |
| Grants |
| Agency |
program |
Grant ID |
Grant title |
| National Natural Science Foundation of China (NSFC)
|
|
81802897
|
|
| National Natural Science Foundation of China (NSFC)
|
|
82170631
|
|
| National Natural Science Foundation of China (NSFC)
|
|
81900597
|
|
| National Natural Science Foundation of China (NSFC)
|
|
81901943
|
|
| National Natural Science Foundation of China (NSFC)
|
|
81972286
|
|
| National Natural Science Foundation of China (NSFC)
|
|
81970567
|
|
|
|
| Submitter |
Rong
Li (lirong53@mail.sysu.edu.cn)
|
| Organization |
The Third Affiliated Hospital, Sun Yat-Sen University |
| Submission date |
2024-01-05 |
