Advanced Science,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 13, 2025
Abstract
The
decrease
in
fibroblast
collagen
is
a
primary
contributor
to
skin
aging.
Lactate
can
participate
synthesis
through
lysine
lactylation
by
regulating
gene
transcription.
However,
the
precise
mechanism
which
lactate
influences
requires
further
investigation.
This
study
demonstrates
that
depletion
of
macrophages
mitigates
stimulating
effect
on
fibroblasts.
Through
joint
CUT&Tag
and
RNA‐sequencing
analyses,
feedback
loop
between
H4K12
(H4K12la)
histone
deacetylase
3
(HDAC3)
drives
lactate‐induced
are
identified.
Macrophages
uptake
extracellular
via
monocarboxylate
transporter‐1
(MCT1),
leading
an
up‐regulation
H4K12la
levels
KAT5‐KAT8‐dependent
response
Poly‐L‐Lactic
Acid
(PLLA)
stimulation,
source
low
concentration
persistent
lactate,
thereby
promoting
Furthermore,
enriched
at
promoters
TGF‐β1
TGF‐β3,
enhancing
their
Hyperlactylation
inhibits
expression
eraser
HDAC3,
while
activation
HDAC3
reduces
suppresses
In
conclusion,
this
illustrates
play
critical
role
skin,
targeting
lactate‐H4K12la‐HDAC3‐TGF‐β
axis
may
represent
novel
approach
for
production
combat
Cell Communication and Signaling,
Год журнала:
2023,
Номер
21(1)
Опубликована: Ноя. 3, 2023
Abstract
Cardiovascular
diseases
pose
a
major
threat
worldwide.
Common
cardiovascular
include
acute
myocardial
infarction
(AMI),
heart
failure,
atrial
fibrillation
(AF)
and
atherosclerosis.
Glycolysis
process
often
has
changed
during
these
diseases.
Lactate,
the
end-product
of
glycolysis,
been
overlooked
in
past
but
gradually
identified
to
play
biological
functions
recent
years.
Similarly,
role
lactate
disease
is
being
recognized.
Targeting
production,
regulating
transport,
modulating
circulating
levels
may
serve
as
potential
strategies
for
treatment
future.
The
purpose
this
review
integrate
relevant
clinical
basic
research
on
pathophysiological
years
clarify
important
guide
further
studies
exploring
other
Abstract
Background
Metabolic
reprogramming
and
epigenetic
alterations
contribute
to
the
aggressiveness
of
pancreatic
ductal
adenocarcinoma
(PDAC).
Lactate-dependent
histone
modification
is
a
new
type
mark,
which
links
glycolysis
metabolite
process
lactylation.
However,
role
lactylation
in
PDAC
remains
unclear.
Methods
The
level
was
identified
by
western
blot
immunohistochemistry,
its
relationship
with
overall
survival
evaluated
using
Kaplan-Meier
plot.
participation
growth
progression
confirmed
through
inhibition
inhibitors
or
lactate
dehydrogenase
A
(
LDHA
)
knockdown
both
vitro
vivo.
potential
writers
erasers
were
functional
experiments.
target
genes
H3K18
(H3K18la)
screened
CUT&Tag
RNA-seq
analyses.
candidate
TTK
protein
kinase
BUB1
mitotic
checkpoint
serine/threonine
B
BUB1B
validated
ChIP-qPCR,
RT-qPCR
Next,
effects
these
two
overexpression.
interaction
between
Co-IP
assay.
Results
Histone
lactylation,
especially
H3K18la
elevated
PDAC,
high
associated
poor
prognosis.
suppression
glycolytic
activity
different
kinds
contributed
anti-tumor
E1A
binding
p300
(P300)
deacetylase
2
writer
eraser
cells,
respectively.
enriched
at
promoters
activated
transcription
regulators
.
Interestingly,
could
elevate
expression
P300
turn
increased
glycolysis.
Moreover,
phosphorylated
tyrosine
239
(Y239)
LDHA,
subsequently
upregulated
levels.
Conclusions
glycolysis-H3K18la-TTK/BUB1B
positive
feedback
loop
exacerbates
dysfunction
PDAC.
These
findings
delivered
exploration
significant
inter-relationship
metabolic
regulation,
might
pave
way
toward
novel
treatment
strategies
therapy.
Lactate
plays
a
critical
role
as
an
energy
substrate,
metabolite,
and
signaling
molecule
in
hepatocellular
carcinoma
(HCC).
Intracellular
lactate-derived
protein
lysine
lactylation
(Kla)
is
identified
contributor
to
the
progression
of
HCC.
Liver
cancer
stem
cells
(LCSCs)
are
believed
be
root
cause
phenotypic
functional
heterogeneity
However,
impact
Kla
on
biological
processes
LCSCs
remains
poorly
understood.
Here
enhanced
glycolytic
metabolism,
lactate
accumulation,
elevated
levels
observed
compared
HCC
cells.
H3K56la
was
found
closely
associated
with
tumourigenesis
stemness
LCSCs.
Notably,
comprehensive
examination
lactylome
proteome
ALDOA
K230/322
lactylation,
which
promoting
Furthermore,
this
study
demonstrated
tight
binding
between
aldolase
A
(ALDOA)
dead
box
deconjugate
enzyme
17
(DDX17),
attenuated
by
ultimately
enhancing
regulatory
function
DDX17
maintaining
This
investigation
highlights
significance
modulating
its
Targeting
may
offer
promising
therapeutic
approach
for
treating
Cell Metabolism,
Год журнала:
2024,
Номер
36(8), С. 1696 - 1710.e10
Опубликована: Авг. 1, 2024
Patients
with
high
ALDH1A3-expressing
glioblastoma
(ALDH1A3hi
GBM)
show
limited
benefit
from
postoperative
chemoradiotherapy.
Understanding
the
mechanisms
underlying
such
resistance
in
these
patients
is
crucial
for
development
of
new
treatments.
Here,
we
that
interaction
between
ALDH1A3
and
PKM2
enhances
latter's
tetramerization
promotes
lactate
accumulation
stem
cells
(GSCs).
By
scanning
lactylated
proteome
lactate-accumulating
GSCs,
XRCC1
undergoes
lactylation
at
lysine
247
(K247).
Lactylated
shows
a
stronger
affinity
importin
α,
allowing
greater
nuclear
transposition
enhanced
DNA
repair.
Through
high-throughput
screening
small-molecule
library,
D34-919
potently
disrupts
ALDH1A3-PKM2
interaction,
preventing
ALDH1A3-mediated
enhancement
tetramerization.
In
vitro
vivo
treatment
chemoradiotherapy-induced
apoptosis
GBM
cells.
Together,
our
findings
potential
therapeutic
target
to
improve
response
chemoradiotherapy
ALDH1A3hi
GBM.
Cellular & Molecular Biology Letters,
Год журнала:
2024,
Номер
29(1)
Опубликована: Фев. 5, 2024
Abstract
For
decades,
lactate
has
been
considered
a
byproduct
of
glycolysis.
The
shuttle
hypothesis
shifted
the
paradigm,
demonstrating
that
not
only
plays
important
roles
in
cellular
metabolism
but
also
communications,
which
can
transcend
compartment
barriers
and
occur
within
among
different
cells,
tissues
organs.
Recently,
discovery
induce
novel
post-translational
modification,
named
lysine
lactylation
(Kla),
brings
forth
new
avenue
to
study
nonmetabolic
functions
for
lactate,
inspired
‘gold
rush’
academic
commercial
interest.
Zhang
et
al.
first
showed
Kla
is
manifested
histones
as
epigenetic
marks,
then
mounting
evidences
demonstrated
occurs
diverse
non-histone
proteins.
widespread
faithfully
orchestrates
numerous
biological
processes,
such
transcription,
inflammatory
responses.
Notably,
dysregulation
touches
myriad
pathological
processes.
In
this
review,
we
comprehensively
reviewed
curated
existing
literature
retrieve
identified
sites
on
both
proteins
summarized
recent
major
advances
toward
its
regulatory
mechanism.
We
thoroughly
investigated
function
underlying
signaling
pathway
summarize
how
regulates
various
processes
normal
physiological
states.
addition,
further
highlight
effects
development
human
diseases
including
inflammation
response,
tumorigenesis,
cardiovascular
nervous
system
other
complex
diseases,
might
potentially
contribute
deeply
understanding
interpreting
mechanism
pathogenicity.
Graphical
Myocardial
ischemia/reperfusion
(MI/R)
injury
is
a
major
cause
of
adverse
outcomes
revascularization
following
myocardial
infarction.
Anaerobic
glycolysis
during
ischemia
well-studied,
but
the
role
aerobic
early
phase
reperfusion
incompletely
understood.
Lactylation
Histone
H3
(H3)
an
epigenetic
indicator
glycolytic
switch.
Heat
shock
protein
A12A
(HSPA12A)
atypic
member
HSP70
family.
In
present
study,
we
report
that
ischemia,
HSPA12A
was
downregulated
and
flux
decreased
in
cardiomyocytes.
Notably,
knockout
mice
exacerbated
MI/R-induced
decrease,
cardiomyocyte
death,
cardiac
dysfunction.
Gain-
loss-of-function
studies
demonstrated
required
to
support
survival
upon
hypoxia/reoxygenation
(H/R)
challenge,
its
protective
effects
were
mediated
by
maintaining
homeostasis
for
lactylation.
Further
analyses
revealed
increased
Smurf1-mediated
Hif1α
stability,
thus
increasing
gene
expression
maintain
appropriate
activity
sustain
lactylation
reperfusion,
ultimately
improving
attenuate
MI/R
injury.
Signal Transduction and Targeted Therapy,
Год журнала:
2025,
Номер
10(1)
Опубликована: Фев. 11, 2025
Abstract
Accumulated
evidence
has
implicated
the
diverse
and
substantial
influence
of
lactate
on
cellular
differentiation
fate
regulation
in
physiological
pathological
settings,
particularly
intricate
conditions
such
as
cancer.
Specifically,
been
demonstrated
to
be
pivotal
molding
tumor
microenvironment
(TME)
through
its
effects
different
cell
populations.
Within
cells,
impacts
signaling
pathways,
augments
shuttle
process,
boosts
resistance
oxidative
stress,
contributes
lactylation.
In
various
populations,
interplay
between
immune
cells
governs
processes
differentiation,
response,
surveillance,
treatment
effectiveness.
Furthermore,
communication
stromal/endothelial
supports
basal
membrane
(BM)
remodeling,
epithelial-mesenchymal
transitions
(EMT),
metabolic
reprogramming,
angiogenesis,
drug
resistance.
Focusing
production
transport,
specifically
dehydrogenase
(LDH)
monocarboxylate
transporters
(MCT),
shown
promise
Inhibitors
targeting
LDH
MCT
act
both
suppressors
enhancers
immunotherapy,
leading
a
synergistic
therapeutic
effect
when
combined
with
immunotherapy.
The
review
underscores
importance
progression
provides
valuable
perspectives
potential
approaches
that
target
vulnerability
metabolism,
highlighting
Heel
Achilles
for
cancer
treatment.
