1) GPX4 ????????????? (GSH) ?????????????????????????? ?????????? MD ???????????????????????? Nature ?????????? “DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer” ?????????????????????????????§à????????????????????????? (DHODH) ?ùy????????????????????????????????? DHODH ?????????2???? ? 1. GPX4??FSP1 ?? DHODH ???????????????[1] ?? DHODH ???????????????? ? 2. a: ???????????????????; b: RSL3 ??/?? Liproxstatin-1 (Lip-1) ????? HT-1080 ????§Ö? 15N-UMP ??; c: ?????C-Asp??DHO??OA??uridine ??????RSL3 ???? NCI-H226 ????????[1] ??????????? DHODH ???????? GPX4 ??????????????????????????????????????????????? DHODH ?? CoQ ?????????????????????????????????????? DHODH ????????????§Ö? CoQ ???? CoQH2 ?????????????? ? 5. a: shControl HT-1080??b: shGPX4 HT-1080??c: NCI-H226 ????????????????[1] ??? DHODH ???????? GPX4 ?????????????????????????????????????§Ö??????????????????¡¤??????????????????????????????¡¤????????¡¤????????????????????????????????????¦Ì???????????????????????????????? DHODH ???????????????????????????????? DHODH ????? ??§¹?? DHODH ???????????? DHODH IC50 ?? 5.2 nM????????????????????? DHODH ?????????????????????????§á?????????¨¢? DHODH ???????????????????§¹???? T ????? B ???????? Ferroptosis ???????????? GPX4 ?????????????? GPX4 ????????????????????????????? Ferroptosis ?????????§¹?? Raf ????????????????? (autophagy) ????? (apoptosis)???????§á?????????? Ferroptosis ?????????????? (autophagy)???????????????????? Ferroptosis ???????????????????????????????????? (VDAC2/VDAC3)?? Ferroptosis ????? ?????? Ferroptosis ???????????????????????????????????????????????????????????????????????§á????????? Ferroptosis ????????????§¹?????????ATP??????? JNK ??????????????? (autophagy)????????? (apoptosis)?? ?????§¹?? ferroptosis ??????????? ferroptotic ??????? (IC50=22 nM)?? ????? 500+ ?? ferroptosis ????????????????????????????????????§à??? MCE ?????§Ó????????????§à????????????????¦Ê¦È???????????????? DHO: Dihydroorotate OA: Orotate ?¦Ï????? 1. Chao Mao, Boyi Gan, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. 2021 May 12.
???????? DHODH ?????????? class 2 ??????????? (RSL3 ?? ML162?????? GPX4 ????) ?? class 1 ??????????? (Sulfasalazine ?? Erastin????? SLC7A11 ?ùy??????????) ????????????????? DHODH ????? GPX4low ??????§Ö????????????? GPX4high ???????????????§³?
????GPX4 ????????? DHODH ??????????????????????????????? DHODH ?¨®?????§Ó?????????????????????????? GPX4 ?¨®???????§Ó????????DHODH ?? GPX4 ?????????????????????????????????öã?????????? DHODH ?????????? GPX4 ?????????????????????? GPX4 ?? FSP1???????DHODH ????? GPX4low ????? (?? GPX4 ???? GPX4high ?????) ?§Ö?????????
????????????????????????????????????????????????????§Ø?????¦Ë??????????????§Ö? GPX4???????? FSP1 ?????????§Ö? DHODH??
Ferroptosis ?????
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GPX4: Glutathione peroxidase 4
FSP1: Ferroptosis suppressor protein 1
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