Iron
catalyses
the
oxidation
of
lipids
in
biological
membranes
and
promotes
a
form
cell
death
called
ferroptosis1.
Defining
where
this
chemistry
occurs
can
inform
design
drugs
capable
inducing
or
inhibiting
ferroptosis
various
disease-relevant
settings.
Genetic
approaches
have
revealed
suppressors
ferroptosis2-4;
by
contrast,
small
molecules
provide
spatiotemporal
control
at
work5.
Here
we
show
that
inhibitor
liproxstatin-1
exerts
cytoprotective
effects
inactivating
iron
lysosomes.
We
also
inducer
RSL3
initiates
membrane
lipid
designed
small-molecule
activator
lysosomal
iron-fentomycin-1-to
induce
oxidative
degradation
phospholipids
ultimately
ferroptosis.
Fentomycin-1
is
able
to
kill
iron-rich
CD44high
primary
sarcoma
pancreatic
ductal
adenocarcinoma
cells,
which
promote
metastasis
fuel
drug
tolerance.
In
such
regulates
adaptation6,7
while
conferring
vulnerability
ferroptosis8,9.
Sarcoma
cells
exposed
sublethal
doses
fentomycin-1
acquire
ferroptosis-resistant
state
characterized
downregulation
mesenchymal
markers
activation
membrane-damage
response.
This
phospholipid
degrader
eradicate
drug-tolerant
persister
cancer
vitro
reduces
intranodal
tumour
growth
mouse
model
breast
metastasis.
Together,
these
results
reactivity
confers
therapeutic
benefits,
establish
as
druggable
target
highlight
value
targeting
states10.
International Journal of Molecular Sciences,
Год журнала:
2022,
Номер
24(1), С. 449 - 449
Опубликована: Дек. 27, 2022
Regulated
cell
death
(RCD)
has
a
significant
impact
on
development,
tissue
homeostasis,
and
the
occurrence
of
various
diseases.
Among
different
forms
RCD,
ferroptosis
is
considered
as
type
reactive
oxygen
species
(ROS)-dependent
regulated
necrosis.
ROS
can
react
with
polyunsaturated
fatty
acids
(PUFAs)
lipid
(L)
membrane
via
formation
radical
L•
induce
peroxidation
to
form
L-ROS.
Ferroptosis
triggered
by
an
imbalance
between
hydroperoxide
(LOOH)
detoxification
iron-dependent
L-ROS
accumulation.
Intracellular
iron
accumulation
are
two
central
biochemical
events
leading
ferroptosis.
Organelles,
including
mitochondria
lysosomes
involved
in
regulation
metabolism
redox
In
this
review,
we
will
provide
overview
peroxidation,
well
key
components
ferroptotic
cascade.
The
main
mechanism
that
reduces
ability
glutathione
(GSH).
GSH,
tripeptide
includes
glutamic
acid,
cysteine,
glycine,
acts
antioxidant
substrate
peroxidase
4
(GPX4),
which
then
converted
into
oxidized
(GSSG).
Increasing
expression
GSH
inhibit
We
highlight
role
xc-
GSH-GPX4
pathway
regulate
system
xc-,
composed
subunit
solute
carrier
family
members
(SLC7A11
SLC3A2),
mediates
exchange
cystine
glutamate
across
plasma
synthesize
GSH.
Accumulating
evidence
indicates
requires
autophagy
machinery
for
its
execution.
Ferritinophagy
used
describe
removal
major
storage
protein
ferritin
machinery.
Nuclear
receptor
coactivator
(NCOA4)
cytosolic
bind
subsequent
degradation
ferritinophagy.
During
ferritinophagy,
stored
released
becomes
available
biosynthetic
pathways.
dysfunctional
response
implicated
variety
pathological
conditions.
inducers
or
inhibitors
targeting
redox-
metabolism-related
proteins
signal
transduction
have
been
developed.
simultaneous
detection
intracellular
extracellular
markers
may
help
diagnose
treat
diseases
related
damage.
Journal of the American Chemical Society,
Год журнала:
2023,
Номер
145(6), С. 3736 - 3747
Опубликована: Фев. 2, 2023
Ferroptosis,
a
newly
discovered
form
of
regulated
cell
death,
is
emerging
as
promising
approach
to
tumor
therapy.
However,
the
spatiotemporal
control
cell-intrinsic
Fenton
chemistry
modulate
ferroptosis
remains
challenging.
Here,
we
report
an
oxazine-based
activatable
molecular
assembly
(PTO-Biotin
Nps),
which
capable
triggering
lysosomal
dysfunction-mediated
pathway
with
excellent
resolution
via
near-infrared
(NIR)
light
evoke
ferroptosis.
In
this
system,
pH-responsive
NIR
photothermal
oxazine
molecule
was
designed
and
functionalized
tumor-targeting
hydrophilic
biotin-poly(ethylene
glycol)
(PEG)
chain
engineer
well-defined
nanostructured
assemblies
within
single-molecular
framework.
PTO-Biotin
Nps
possesses
selective
tropism
lysosome
accumulation
inside
cells,
accommodated
by
its
enhanced
activity
in
acidic
microenvironment.
Upon
activation,
promoted
dysfunction
induced
cytosolic
acidification
impaired
autophagy.
More
importantly,
photoactivation-mediated
found
markedly
enhance
cellular
reactions
ferroptosis,
thereby
improving
antitumor
efficacy
mitigating
systemic
side
effects.
Overall,
our
study
demonstrates
that
engineering
enables
modulation
intrinsic
mechanism,
offering
novel
strategy
for
development
metal-free
inducers
Molecular Psychiatry,
Год журнала:
2024,
Номер
29(4), С. 1139 - 1152
Опубликована: Янв. 12, 2024
Iron
is
an
essential
element
for
the
development
and
functionality
of
brain,
anomalies
in
its
distribution
concentration
brain
tissue
have
been
found
to
be
associated
with
most
frequent
neurodegenerative
diseases.
When
magnetic
resonance
techniques
allowed
iron
quantification
vivo,
it
was
confirmed
that
alteration
homeostasis
a
common
feature
many
However,
whether
main
actor
process,
or
consequence
degenerative
process
still
open
question.
Because
different
iron-related
pathogenic
mechanisms
are
specific
distinctive
diseases,
identifying
molecular
various
pathologies
could
represent
way
clarify
this
complex
topic.
Indeed,
both
overload
deficiency
profound
consequences
on
cellular
functioning,
contribute
neuronal
death
processes
manners,
such
as
promoting
oxidative
damage,
loss
membrane
integrity,
proteostasis,
mitochondrial
dysfunction.
In
review,
attempt
elucidate
dyshomeostasis
health,
we
summarize
pathological
couple
death.
Advanced Materials,
Год журнала:
2024,
Номер
36(21)
Опубликована: Фев. 10, 2024
Abstract
Immunotherapy
has
received
widespread
attention
for
its
effective
and
long‐term
tumor‐eliminating
ability.
However,
immunogenic
“cold”
tumors,
such
as
prostate
cancer
(PCa),
the
low
immunogenicity
of
tumor
itself
is
a
serious
obstacle
to
efficacy.
Here,
this
work
reports
strategy
enhance
PCa
by
triggering
cascade
self‐enhanced
ferroptosis
in
cells,
turning
from
“hot”.
This
develops
transformable
self‐assembled
peptide
TEP‐FFG‐CRApY
with
alkaline
phosphatase
(ALP)
responsiveness
glutathione
peroxidase
4
(GPX4)
protein
targeting.
self‐assembles
into
nanoparticles
under
aqueous
conditions
transforms
nanofibers
response
ALP
during
endosome/lysosome
uptake
promoting
lysosomal
membrane
permeabilization
(LMP).
On
one
hand,
released
TEP‐FFG‐CRAY
target
GPX4
selectively
degrade
light
irradiation,
inducing
ferroptosis;
on
other
large
amount
leaked
Fe
2+
further
amplify
through
Fenton
reaction.
TEP‐FFG‐CRApY‐induced
improves
cell
maturation
dendritic
cells
(DCs)
increasing
intratumor
T‐cell
infiltration.
More
importantly,
recovered
T
secreting
amounts
interferon‐gamma
(IFN‐γ).
provides
novel
molecular
design
synergistic
molecularly
targeted
therapy
tumors.
Cell Death and Disease,
Год журнала:
2024,
Номер
15(11)
Опубликована: Ноя. 26, 2024
Abstract
Regulated
cell
death
(RCD)
refers
to
the
form
of
that
can
be
regulated
by
various
biomacromolecules.
Each
modalities
have
their
distinct
morphological
changes
and
molecular
mechanisms.
However,
intense
evidences
suggest
lipid
peroxidation
common
feature
initiates
propagates
death.
Excessive
alters
property
membrane
further
damage
proteins
nucleic
acids,
which
is
implicated
in
human
pathologies.
Here,
we
firstly
review
classical
chain
process
peroxidation,
clarify
current
understanding
myriad
roles
mechanisms
RCD
types.
We
also
discuss
how
involves
diseases
such
intimate
association
between
peroxidation-driven
leveraged
develop
rational
therapeutic
strategies.
Chemical Reviews,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 2, 2025
Complex
multicellular
organisms
are
composed
of
distinct
tissues
involving
specialized
cells
that
can
perform
specific
functions,
making
such
life
forms
possible.
Species
defined
by
their
genomes,
and
differences
between
individuals
within
a
given
species
directly
result
from
variations
in
genetic
codes.
While
alterations
give
rise
to
disease-causing
acquisitions
cell
identities,
it
is
now
well-established
biochemical
imbalances
also
lead
cellular
dysfunction
diseases.
Specifically,
nongenetic
chemical
events
orchestrate
metabolism
transcriptional
programs
govern
functional
identity.
Thus,
signaling,
which
broadly
defines
the
conversion
extracellular
signals
into
intracellular
changes,
contribute
acquisition
diseased
states.
Metal
ions
exhibit
unique
properties
be
exploited
cell.
For
instance,
metal
maintain
ionic
balance
cell,
coordinate
amino
acid
residues
or
nucleobases
altering
folding
function
biomolecules,
catalyze
reactions.
metals
essential
signaling
effectors
normal
physiology
disease.
Deciphering
ion
challenging
endeavor
illuminate
pathways
targeted
for
therapeutic
intervention.
Here,
we
review
key
processes
where
play
roles
describe
how
targeting
has
been
instrumental
dissecting
biochemistry
this
led
development
effective
strategies.