families as new metagenomes were added to present and how abundant they are (the taxo- Duisburg-Essen, Essen,

isburg-Essen, Essen, 45141, Germany.

their analysis. Instead, the detection of protein nomic composition), and examining genes that e-mail: alexander.probst@uni-due.de
families increased exponentially, warranting are associated with certain functions. Finding
an array of follow-on studies. specific but differentially abundant protein
The distribution of protein families across families of unknown function, as demonstrated 1. Rodríguez del Río, A. et al. Nature 626, 377–384 (2024).
Earth’s categories of ecosystem (biomes) by Rodríguez del Río and co-workers, has the 2. Vanni, C. et al. eLife 11, e67667 (2022).
3. Pavlopoulos, G. A. et al. Nature 622, 594–602 (2023).
presented by Pavlopoulos and colleagues potential not only to replace current marker- 4. Jumper, J. et al. Nature 596, 583–589 (2021).
corroborates the findings of previous investi- gene-based approaches for differentiating 5. Doron, S. et al. Science 359, eaar4120 (2018).
gations regarding the distribution of microbial microbiomes but also to advance microbiome 6. Illergård, K., Ardell, D. H. & Elofsson, A. Proteins 77,
499–508 (2009).
genes8. Some biological entities, however, research to a new and causality-driven level. 7. Tyson, G. W. et al. Nature 428, 37–43 (2004).
were particularly rich sources of newly dis- 8. Coelho, L. P. et al. Nature 601, 252–256 (2022).
covered protein families, including viruses, as Alexander J. Probst is in the Research Center 9. Eme, L. et al. Nature 618, 992–999 (2023).

Pavlopoulos et al. report, and microbes called One Health Ruhr, University Alliance Ruhr, The authors declare no competing interests.
Asgardarchaeota, as presented by Rodríguez Department of Chemistry at University of This article was published online on 30 January 2024.
del Río and colleagues. The latter are a group
of microorganisms called archaea that are
Cancer
closely related to the first ancestor of eukar-

Natural inhibitor found for

yotes. As such, studying their proteins might
reveal new insights into the evolution of the
eukaryotic cell9.
One major challenge in exploring the
wealth of previously unknown protein fami- cell death by ferroptosis
lies encoded in genomes of natural samples
is the identification of eukaryotic genes in
Donna D. Zhang
metagenomes. Although certain algorithms
exist for the recovery of eukaryotic genomes The discovery that an evolutionarily conserved molecule used
from metagenomes, accurately predicting to make cholesterol also acts as a defence against a cell-death
eukaryotic genes in mixed DNA sequences
— equivalent to Pavlopoulos and colleagues’
mechanism called ferroptosis might lead to new ways to treat
method of identifying microbial genes — is still cancer and other clinical conditions. See p.401 & p.411
not possible bioinformatically. Once this short-
coming is overcome with the development of
new algorithms, scientists will substantially Biology remains nothing short of astonish- of ferroptosis. However, one of the enzymes,
expand the protein ‘sequence space’ and will ing, as researchers unveil the underpinnings DHCR7, which catalyses the reaction that
identify protein families of unknown func- of its myriad systems, especially those that are converts 7-DHC to cholesterol, was found
tion that drive the ecology and evolution of involved in protecting against cell death. On to promote ferroptosis. This indicates that
eukaryotes. pages 401 and 411, respectively, Freitas et al.1 7-DHC, produced by the enzyme SC5D and
The greatest advance in painstakingly and Li et al.2 shed light on a regulated form of used by DHCR7, operates as a key protection
organizing the protein families of nearly cell death called ferroptosis, which is driven against ferroptosis.
27,000 metagenomes and across the tree of life by an iron-dependent modification of lipids Both teams then explored the mechanism
lies in the identification of ecosystem-specific in cellular membranes. The results bring into of action of 7-DHC in more detail. They high-
protein clusters that differ in terms of their sharp focus an unexpected hero, the molecule lighted a key characteristic of its structure — a
presence or absence, or relative abundance 7-dehydrocholesterol (7-DHC). part that is described as a conjugated double
between varying conditions of a given eco- The term ferroptosis was coined in 2012 bond in the sterol B-ring. This component
system — for example, between the contexts (ref. 3). This cell death encompasses a variety of its structure enables 7-DHC to absorb
of health or disease. Applying this strategy to of processes that include lipid oxidation by the radicals, thereby reducing lipid fragmenta-
examine microbial data for healthy people action of reactive molecules called radicals tion driven by an oxidation process called
and those with colorectal cancer, Rodríguez (versions of molecules that have an unpaired peroxidation.
del Río and colleagues found that specific electron) and the fragmentation of lipids at cel- Both teams recognized that it is mainly lipid
unknown protein families were enriched in lular membranes, culminating in membrane components called phospholipids — espe-
the gut bacteria of people with cancer. These disruption, shrunken mitochondrial organelles cially if these are fragmented into smaller
protein families were associated with micro- and swelling of cells (‘ballooning’). Ferroptosis pieces — that can initiate ferroptosis. These
bial motility, adhesion and invasion poten- occurs when there are problems in the regula- findings underscore the protective function
tially of human tissue, as revealed through tion of normal iron levels (iron homeostasis) of 7-DHC, especially in scenarios in which
genomic-context analysis. Harnessing this and in the oxidation of lipids. Preventing ferrop- ferroptosis might otherwise occur if this
approach in other fields of research should tosis might be beneficial in alleviating neurode- molecule wasn’t present.
be extremely helpful for deciphering the dif- generative and kidney diseases, and activation Most remarkably, the two teams also found
ferent functions of sample sets, in the hope of ferroptosis can kill cancer cells4–7. that the molecule ergosterol, which is found
of identifying new targets for biochemical Freitas et al. and Li et al. report that 7-DHC, a in yeast and fungi and has structural similar-
analyses to shed light on a tiny fraction of the molecule in the cholesterol-synthesis pathway ity to 7-DHC, also offers protection against
microbial dark matter. (Fig. 1), acts to suppress ferroptosis. Both teams ferroptosis. This finding suggests that the
Identifying differences in microbial com- independently discovered the anti-ferroptotic anti-ferroptotic effect of a molecule in the
munities (microbiomes) that might explain, role of the cholesterol-synthesis pathway. The cholesterol-synthesis pathway might be evo-
for example, the disease state of a person, authors reveal that several enzymes in this lutionarily conserved, serving to safeguard a
rely heavily on comparing which species are pathway function as potential suppressors variety of organisms from ferroptosis.

Nature | Vol 626 | 8 February 2024 | 269

News & views

Fragmented lipid
leads to cell rupture
HMG-CoA
and ferroptosis Radical
Intact
phospholipid
Zymosterol Phospholipid 7-DHC

EBP Radical absorbed

by 7-DHC
Lathosterol Oxidized
SC5D Cell phospholipid Lipid
membrane ROS free Iron
7-DHC fragmentation
radical
suppressed
DHCR7 Lipid
fragmentation
Cholesterol

ER

Mitochondrion

Figure 1 | A molecule that can help to halt cell death by ferroptosis. A membrane and in another type of organelle, known as mitochondria. 7-DHC is
hallmark of ferroptosis is lipid modification (oxidation) mediated by iron and generated in the pathway (not all steps of which are shown) that converts the
molecules called free radicals, such as reactive oxygen species (ROS). Oxidation molecule HMG-CoA to cholesterol through a route that includes the molecules
of lipids, particularly of those called phospholipids, in cellular membranes zymosterol and lathosterol and depends on enzymes such as EBP, SC5D
can kill cells. Freitas et al.1 and Li et al.2 report a previously unknown natural and DHCR7. When radicals attack phospholipids, the lipid is oxidized and it
inhibitor of ferroptosis. This molecule, 7-dehydrocholesterol (7-DHC), is made fragments. 7-DHC absorbs radicals, counteracting their ability to trigger lipid
in an organelle called the endoplasmic reticulum (ER) and found on the cell oxidation and ferroptosis.

The discovery of a natural inhibitor of Building on their initial findings, Li and col- is validated in clinical testing. However,
ferroptosis has profound therapeutic impli- leagues examined 7-DHC’s role in metastasis. previous research8,9 indicates that excessive
cations. By modulating the levels of 7-DHC, The authors hypothesized that before spread- levels of 7-DHC and the products arising from
there is the potential to either induce or ing to distant organs, cancer cells need to modifications (oxidation) of this molecule
counteract ferroptosis. Investigating the endure environments that have a condition might be detrimental, particularly to neu-
role of 7-DHC in human cancers, Freitas and (oxidative stress) that predisposes the cells ronal and retinal cells. Thoroughly examining
colleagues observed that 9.8% of individu- to ferroptosis. Li et al. used a combination of the implications for brain and eye health will
als studied who had Burkitt’s lymphoma had approaches to investigate this. These included be crucial before incorporating any 7-DHC-
mutations in the DHCR7 gene, which encodes deleting the DHCR7 gene, inhibiting DHCR7 based therapeutic strategies into standard
the corresponding enzyme. The authors note with the drug AY9944, pretreating melanoma clinical practice.
a less-frequent occurrence of such mutations cancer cells with 7-DHC to elevate 7-DHC levels
in people who have a brain cancer called and using TASIN-30 to hinder 7-DHC synthe- Donna D. Zhang is in the Center for
neuroblastoma. sis. These approaches establish that 7-DHC Inflammation Science and Systems Medicine,
The deletion of DHCR7 by Li and colleagues The Herbert Wertheim University of Florida
increased 7-DHC levels, bolstering the “Harnessing this new Scripps Institute for Biomedical Innovation
resistance of neuroblastoma cancer cells and Technology, Jupiter, Florida 33458, USA.
to ferroptosis when tested in vitro. In vivo
understanding with e-mail: zhangd1@ufl.edu
experiments in mice showed that these engi- available tools holds the
neered human neuroblastoma cells evaded potential to transform
ferroptotic death, leading to faster tumour
growth, increased tumour spread (metastasis)
clinical treatments.”
and decreased survival time compared with
results from mice in which the transplanted can fortify melanoma cells, enhancing their
cells expressed DHCR7. survival and accelerating metastasis.
Li et al. present evidence of the effect of Using a mouse model of tissue injury, Li and
manipulating 7-DHC levels. They report that colleagues demonstrated that the accumula-
inhibiting 7-DHC synthesis by targeting an tion of 7-DHC could be amplified by inhibiting
enzyme called EBP in the cholesterol-synthesis DHCR7, achieved through pre-injury injections
pathway with the molecule TASIN-30 induced of DHCR7 inhibitors. This intervention effec-
1. Freitas, F. P. et al. Nature 626, 401–410 (2024).
ferroptosis. This led to the suppression of tively shielded against injury by preventing 2. Li, Y. et al. Nature 626, 411–418 (2024).
tumour growth in vivo when human cancer ferroptotic death of kidney cells. 3. Dixon, S. J. et al. Cell 149, 1060–1072 (2012).
cells with high levels of 7-DHC were injected The discovery of 7-DHC’s role in prevent- 4. Stockwell, B. R. et al. Cell 171, 273–285 (2017).
5. Galy, B., Conrad, M. & Muckenthaler, M. Nature Rev. Mol.
into mice. It is notable that this cell-death sup- ing ferroptosis is a key leap forwards in this Cell Biol. 25, 133–155 (2024).
pression occurred even in the absence of other area. The therapeutic potential of the finding 6. Anandhan, A. et al. Sci. Adv. 9, eade9585 (2023).
ferroptosis inducers besides TASIN-30, under- is strikingly evident. Given the availability 7. Conrad, M., Angeli, J. P. F., Vandenabeele, P. & Stockwell,
B. R. Nature Rev. Drug Discov. 15, 348–366 (2016).
scoring the key role of 7-DHC in providing pro- of drugs already in clinical use to target 8. Xu, L. et al. Neurobiol. Dis. 45, 923–929 (2012).
tection against cell death for certain cancer DHCR7, harnessing this new understanding 9. Pfeffer, B. A., Xu, L., Porter, N. A., Rao, S. R. & Fliesler, S. J.
types. This protective mechanism makes these with available tools holds the potential to Exp. Eye Res. 145, 297–316 (2016).

cancer cells susceptible to drugs that inhibit transform clinical treatments for conditions The author declares no competing interests.
7-DHC production. influenced by ferroptosis, if this approach This article was published online on 31 January 2024.

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