Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO2 is an endoperoxide-containing 1,2-dioxolane that can initiate ferroptosis selectively in engineered cancer cells. We investigated the mechanism and structural features necessary for ferroptosis initiation by FINO2. We found that FINO2 requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO2 does not inhibit system xc− or directly target GPX4, as do erastin and RSL3, respectively, or deplete GPX4 protein, as does FIN56. Instead, FINO2 causes both indirect loss of GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multi-pronged mechanism of ferroptosis.

Highlights d 3F3-FMA is identified in a screen as a selective ferroptosisimmunostaining reagent d The antigen of 3F3-FMA is identified as the transferrin receptor 1 protein (TfR1) d Anti-TfR1 antibodies can detect ferroptosis by immunofluorescence and flow cytometry d Anti-TfR1 and anti-MDA antibodies detect ferroptosis in xenograft cancer models

MDM2 and MDMX, negative regulators of the tumor suppressor p53, can work separately and as a heteromeric complex to restrain p53's functions. MDM2 also has pro-oncogenic roles in cells, tissues, and animals that are independent of p53. There is less information available about p53-independent roles of MDMX or the MDM2-MDMX complex. We found that MDM2 and MDMX facilitate ferroptosis in cells with or without p53. Using small molecules, RNA interference reagents, and mutant forms of MDMX, we found that MDM2 and MDMX, likely working in part as a complex, normally facilitate ferroptotic death. We observed that MDM2 and MDMX alter the lipid profile of cells to favor ferroptosis. Inhibition of MDM2 or MDMX leads to increased levels of FSP1 protein and a consequent increase in the levels of coenzyme Q 10 , an endogenous lipophilic antioxidant. This suggests that MDM2 and MDMX normally prevent cells from mounting an adequate defense against lipid peroxidation and thereby promote ferroptosis. Moreover, we found that PPARα activity is essential for MDM2 and MDMX to promote ferroptosis, suggesting that the MDM2-MDMX complex regulates lipids through altering PPARα activity. These findings reveal the complexity of cellular responses to MDM2 and MDMX and suggest that MDM2-MDMX inhibition might be useful for preventing degenerative diseases involving ferroptosis. Furthermore, they suggest that MDM2/MDMX amplification may predict sensitivity of some cancers to ferroptosis inducers.

In the present paper we describe the basic results of long-term selection for low yolk cholesterol content in Japanese quail and its influence on development and relationship with other egg quality traits during nineteen selected generations. The changes in a selected low cholesterol line were compared with changes in an unselected control line to obtain the real selection response to estimated traits. There was a significant decrease in yolk cholesterol content from 1 815 mg/100 g of fresh yolk (P generation) to 1 522 mg/100 g yolk (S19 generation). According to the value of regression coefficient <I>b</I> the decrease per one generation was 15.71 mg/100 g yolk. The decrease in cholesterol of the edible part of egg was also effective and it significantly decreased by 11.29 mg/100 g of the edible part of egg in each generation. There were only insignificant changes in egg weight, but we found a significant increase in yolk weight during selected generations. According to the regression analysis the increase in yolk weight was 0.019 mg/100 g per one generation. There were a positive but insignificant increase also in albumen weight, shell weight and weight of the edible part of egg. We found a small and insignificant decrease in shape index. We determined very high and significant positive correlations between cholesterol content in yolk and cholesterol content in the edible part of egg (0.801+++) and significant negative correlations between yolk cholesterol content and egg weight (–0.515+), yolk weight (–0.468+) and weight of the edible part of egg (–0.475). There were only low, positive and insignificant correlations between yolk cholesterol content and yolk egg proportion and egg shape index.

Cave environments on Earth have long provided shelter to a variety of organisms, from microbes to humans. Though their scales of interest differ vastly, these two examples have sought the same comfort from caves: a stable and sheltered environment, protected from the woes of the surface world. Since the discovery of lava caves on Mars (see Sauro et al., 2020 for a review), they have become of renewed interest as targets for human shelter in future missions, as well as areas of astrobiological interest, with the potential of harboring traces of extant or extinct extraterrestrial life.