Abstract：
Ferroptosis is a type of regulated cell death characterized by iron-dependent lipid peroxidation. A model cell system is constructed to induce ferroptosis by re-expressing the transcription factor BACH1, a potent ferroptosis inducer, in immortalized mouse embryonic fibroblasts (iMEFs). The transfer of the culture supernatant from ferroptotic iMEFs activates the proliferation of hepatoma cells and other fibroblasts and suppresses cellular senescence-like features. The BACH1-dependent secretion of the longevity factor FGF21 is increased in ferroptotic iMEFs. The anti-senescent effects of the culture supernatant from these iMEFs are abrogated by Fgf21 knockout. BACH1 activates the transcription of Fgf21 by promoting ferroptotic stress and increases FGF21 protein expression by suppressing its autophagic degradation through transcriptional Sqstm1 and Lamp2 repression. The BACH1-induced ferroptotic FGF21 secretion suppresses obesity in high-fat diet-fed mice and the short lifespan of progeria mice. The inhibition of these aging-related phenotypes can be physiologically significant regarding ferroptosis.
摘要：
铁凋亡是一种以铁依赖性脂质过氧化为特征的调节性细胞死亡。构建了一个模型细胞系统，通过重新表达有效的铁凋亡诱导剂BACH1转录因子来诱导铁凋亡，在永生化小鼠胚胎成纤维细胞（IMEFs）中。来自铁细胞iMEF的培养上清液的转移激活了肝癌细胞和其他成纤维细胞的增殖，并抑制了细胞衰老样特征。在铁细胞iMEFs中，长寿因子FGF21的BACH1依赖性分泌增加。来自这些iMEF的培养上清液的抗衰老作用通过Fgf21敲除而消除。BACH1通过促进铁应激激活Fgf21的转录，并通过转录Sqstm1和Lamp2抑制抑制其自噬降解来增加FGF21蛋白的表达。BACH1诱导的FGF21分泌抑制高脂饮食小鼠的肥胖和早衰小鼠的短寿命。这些衰老相关表型的抑制对于铁死亡可能是生理上显著的。
