Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones.

Ferroptosis, a cell death process driven by iron-dependent phospholipid peroxidation, has been implicated in various diseases. There are two major surveillance mechanisms to suppress ferroptosis: one mediated by glutathione peroxidase 4 (GPX4) that catalyzes the reduction of phospholipid peroxides and the other mediated by enzymes, such as FSP1, that produce metabolites with free radical-trapping antioxidant activity. In this study, through a whole-genome CRISPR activation screen, followed by mechanistic investigation, we identified phospholipid-modifying enzymes MBOAT1 and MBOAT2 as ferroptosis suppressors. MBOAT1/2 inhibit ferroptosis by remodeling the cellular phospholipid profile, and strikingly, their ferroptosis surveillance function is independent of GPX4 or FSP1. MBOAT1 and MBOAT2 are transcriptionally upregulated by sex hormone receptors, i.e., estrogen receptor (ER) and androgen receptor (AR), respectively. A combination of ER or AR antagonist with ferroptosis induction significantly inhibited the growth of ER+ breast cancer and AR+ prostate cancer, even when tumors were resistant to single-agent hormonal therapies.

Evidence for multiple group 1 late embryogenesis abundant proteins in encysted embryos of Artemia and their organelles.

The presence of late embryogenesis abundant (LEA) proteins in plants and animals has been linked to their ability to tolerate a variety of environmental stresses. Among animals, encysted embryos of the brine shrimp Artemia franciscana are among the most stress resistant eukaryotes, and for that reason it is considered to be an extremophile. The study presented here demonstrates that these embryos contain multiple group 1 LEA proteins with masses of 21, 19, 15.5 and 13 kDa. The LEA proteins first appear in diapause-destined embryos, beginning at ∼4 days post-fertilization, but not in nauplii-destined embryos. After resumption of embryonic development, the LEA proteins decline slowly in the desiccation resistant encysted stages, then disappear rapidly as the embryo emerges from its shell. LEA proteins are absent in fully emerged embryos, larvae and adults. They are abundant in mitochondria of encysted embryos, but barely detectable in nuclei and absent from yolk platelets. LEA proteins were also detected in dormant embryos of six other species of Artemia from hypersaline environments around the world. This study enhances our knowledge of the group 1 LEA proteins in stress tolerant crustacean embryos.