Journal of the American Chemical Society,
Journal Year:
2022,
Volume and Issue:
144(26), P. 11536 - 11545
Published: June 13, 2022
Persister
cancer
cells
represent
rare
populations
of
resistant
to
therapy.
Cancer
can
exploit
epithelial-mesenchymal
plasticity
adopt
a
drug-tolerant
state
that
does
not
depend
on
genetic
alterations.
Small
molecules
interfere
with
cell
or
kill
in
state-dependent
manner
are
highly
sought
after.
Salinomycin
has
been
shown
the
mesenchymal
by
sequestering
iron
lysosomes,
taking
advantage
addiction
this
state.
Here,
we
report
chemo-
and
stereoselective
synthesis
series
structurally
complex
small
molecule
chimeras
salinomycin
derivatives
iron-reactive
dihydroartemisinin.
We
show
these
accumulate
lysosomes
react
release
bioactive
species,
thereby
inducing
ferroptosis
pancreatic
biopsy-derived
organoids
ductal
adenocarcinoma.
This
work
paves
way
toward
development
new
medicines
acting
through
active
ferroptosis.
Nature,
Journal Year:
2022,
Volume and Issue:
608(7924), P. 778 - 783
Published: Aug. 3, 2022
Ferroptosis,
a
non-apoptotic
form
of
cell
death
marked
by
iron-dependent
lipid
peroxidation1,
has
key
role
in
organ
injury,
degenerative
disease
and
vulnerability
therapy-resistant
cancers2.
Although
substantial
progress
been
made
understanding
the
molecular
processes
relevant
to
ferroptosis,
additional
cell-extrinsic
cell-intrinsic
that
determine
sensitivity
toward
ferroptosis
remain
unknown.
Here
we
show
fully
reduced
forms
vitamin
K-a
group
naphthoquinones
includes
menaquinone
phylloquinone3-confer
strong
anti-ferroptotic
function,
addition
conventional
function
linked
blood
clotting
acting
as
cofactor
for
γ-glutamyl
carboxylase.
Ferroptosis
suppressor
protein
1
(FSP1),
NAD(P)H-ubiquinone
reductase
second
mainstay
control
after
glutathione
peroxidase-44,5,
was
found
efficiently
reduce
K
its
hydroquinone,
potent
radical-trapping
antioxidant
inhibitor
(phospho)lipid
peroxidation.
The
FSP1-mediated
reduction
also
responsible
antidotal
effect
against
warfarin
poisoning.
It
follows
FSP1
is
enzyme
mediating
warfarin-resistant
canonical
cycle6.
FSP1-dependent
non-canonical
cycle
can
act
protect
cells
detrimental
peroxidation
ferroptosis.
Nature,
Journal Year:
2023,
Volume and Issue:
619(7969), P. 371 - 377
Published: June 28, 2023
Ferroptosis
is
evolving
as
a
highly
promising
approach
to
combat
difficult-to-treat
tumour
entities
including
therapy-refractory
and
dedifferentiating
cancers1-3.
Recently,
ferroptosis
suppressor
protein-1
(FSP1),
along
with
extramitochondrial
ubiquinone
or
exogenous
vitamin
K
NAD(P)H/H+
an
electron
donor,
has
been
identified
the
second
ferroptosis-suppressing
system,
which
efficiently
prevents
lipid
peroxidation
independently
of
cyst(e)ine-glutathione
(GSH)-glutathione
peroxidase
4
(GPX4)
axis4-6.
To
develop
FSP1
inhibitors
next-generation
therapeutic
inducers,
here
we
performed
small
molecule
library
screen
compound
class
3-phenylquinazolinones
(represented
by
icFSP1)
potent
inhibitors.
We
show
that
icFSP1,
unlike
iFSP1,
first
described
on-target
inhibitor5,
does
not
competitively
inhibit
enzyme
activity,
but
instead
triggers
subcellular
relocalization
from
membrane
condensation
before
induction,
in
synergism
GPX4
inhibition.
icFSP1-induced
condensates
droplet-like
properties
consistent
phase
separation,
emerging
widespread
mechanism
modulate
biological
activity7.
N-terminal
myristoylation,
distinct
amino
acid
residues
intrinsically
disordered,
low-complexity
regions
were
be
essential
for
FSP1-dependent
separation
cells
vitro.
further
demonstrate
icFSP1
impairs
growth
induces
tumours
vivo.
Hence,
our
results
suggest
exhibits
unique
action
synergizes
ferroptosis-inducing
agents
potentiate
ferroptotic
cell
death
response,
thus
providing
rationale
targeting
efficient
anti-cancer
therapy.
Nature,
Journal Year:
2023,
Volume and Issue:
617(7960), P. 386 - 394
Published: April 26, 2023
Abstract
Inflammation
is
a
complex
physiological
process
triggered
in
response
to
harmful
stimuli
1
.
It
involves
cells
of
the
immune
system
capable
clearing
sources
injury
and
damaged
tissues.
Excessive
inflammation
can
occur
as
result
infection
hallmark
several
diseases
2–4
The
molecular
bases
underlying
inflammatory
responses
are
not
fully
understood.
Here
we
show
that
cell
surface
glycoprotein
CD44,
which
marks
acquisition
distinct
phenotypes
context
development,
immunity
cancer
progression,
mediates
uptake
metals
including
copper.
We
identify
pool
chemically
reactive
copper
(ii)
mitochondria
macrophages
catalyses
NAD(H)
redox
cycling
by
activating
hydrogen
peroxide.
Maintenance
NAD
+
enables
metabolic
epigenetic
programming
towards
state.
Targeting
mitochondrial
with
supformin
(LCC-12),
rationally
designed
dimer
metformin,
induces
reduction
pool,
leading
states
oppose
macrophage
activation.
LCC-12
interferes
plasticity
other
settings
reduces
mouse
models
bacterial
viral
infections.
Our
work
highlights
central
role
regulator
unveils
therapeutic
strategy
based
on
reprogramming
control
states.
Redox Biology,
Journal Year:
2024,
Volume and Issue:
75, P. 103211 - 103211
Published: May 30, 2024
Ferroptosis
is
a
pervasive
non-apoptotic
form
of
cell
death
highly
relevant
in
various
degenerative
diseases
and
malignancies.
The
hallmark
ferroptosis
uncontrolled
overwhelming
peroxidation
polyunsaturated
fatty
acids
contained
membrane
phospholipids,
which
eventually
leads
to
rupture
the
plasma
membrane.
unique
that
it
essentially
spontaneous,
uncatalyzed
chemical
process
based
on
perturbed
iron
redox
homeostasis
contributing
process,
but
nonetheless
modulated
by
many
metabolic
nodes
impinge
cells'
susceptibility
ferroptosis.
Among
affecting
sensitivity,
several
have
emerged
as
promising
candidates
for
pharmacological
intervention,
rendering
ferroptosis-related
proteins
attractive
targets
treatment
numerous
currently
incurable
diseases.
Herein,
current
members
Germany-wide
research
consortium
focusing
research,
well
key
external
experts
who
made
seminal
contributions
this
rapidly
growing
exciting
field
gathered
provide
comprehensive,
state-of-the-art
review
Specific
topics
include:
basic
mechanisms,
vivo
relevance,
specialized
methodologies,
tools,
potential
contribution
disease
etiopathology
progression.
We
hope
article
will
not
only
established
scientists
newcomers
with
an
overview
multiple
facets
ferroptosis,
also
encourage
additional
efforts
characterize
further
molecular
pathways
modulating
ultimate
goal
develop
novel
pharmacotherapies
tackle
associated
-
or
caused
