Gut Microbes,
Journal Year:
2025,
Volume and Issue:
17(1)
Published: Jan. 30, 2025
Ischemia-reperfusion
injury
(IRI)
is
a
major
obstacle
in
liver
transplantation,
especially
with
steatotic
donor
livers.
Dysbiosis
of
the
gut
microbiota
has
been
implicated
modulating
IRI,
and
Lachnospiraceae
plays
pivotal
role
regulating
host
inflammatory
immune
responses,
but
its
specific
transplantation
IRI
remains
unclear.
This
study
explores
whether
can
mitigate
underlying
mechanisms.
We
found
Lachnospiraceae-bacterium
(Lachn.)
abundance
was
significantly
reduced
rats
cirrhosis.
Lachn.-treated
exhibited
improved
intestinal
permeability,
severity
both
normal
livers,
decreased
levels
neutrophil
macrophage
infiltration,
cytokines.
Multi-omics
analysis
revealed
elevated
pyruvate
transplanted
livers
after
Lachn.
treatment,
alongside
Alox15
Foxo3
expression.
Mechanistically,
Lachn.-derived
inhibited
expression
ferroptosis
Furthermore,
nuclear
translocation
further
suppressed
expression,
alleviating
Clinical
samples
confirmed
cirrhotic
recipients
high
transplantation.
In
conclusion,
alleviates
by
inhibiting
via
Foxo3-Alox15
axis,
providing
potential
therapeutic
strategy
to
modulate
alleviate
following
Frontiers in Immunology,
Journal Year:
2025,
Volume and Issue:
16
Published: Feb. 17, 2025
Background
Liver
ischemia-reperfusion
injury
(LIRI)
is
a
critical
condition
after
liver
transplantation.
Understanding
the
role
of
immunogenic
cell
death
(ICD)
may
provide
insights
into
its
diagnosis
and
potential
therapeutic
targets.
Methods
Differentially
expressed
genes
(DEGs)
between
LIRI
normal
samples
were
identified,
pathway
enrichment
analyses
performed,
followed
by
immune
infiltration
assessment
through
CIBERSORT
method.
The
consensus
clustering
analysis
was
conducted
to
separate
clusters
single-sample
Gene
Set
Enrichment
Analysis
(ssGSEA)
used
analyze
distinct
states
clusters.
Weighted
Co-Expression
Network
(WGCNA)
employed
identify
hub
associated
with
ICD.
To
establish
diagnostic
models,
four
machine
learning
techniques,
including
Random
Forest
(RF),
XGBoost
(XGB),
Support
Vector
Machine
(SVM),
Generalized
Linear
Models
(GLM),
applied
filter
gene
sets.
receiver
operating
characteristic
(ROC)
curves
utilized
assess
performance
models.
Results
Pathway
results
revealed
significant
involvement
cytokines
chemokines
among
DEGs
LIRI.
Immune
indicated
higher
levels
specific
functions
in
Cluster
2
compared
1.
WGCNA
identified
modules
linked
strong
correlations
module
membership
significance.
RF
SVM
algorithms
finally
chosen
construct
Both
demonstrated
high
predictive
accuracy
for
diagnosing
not
only
training
cohort
GSE151648
but
also
validation
cohorts
GSE23649
GSE15480.
Conclusions
study
highlights
pivotal
roles
ICD-related
LIRI,
providing
models
clinical
applications
early
detection
intervention
strategies
against
Angewandte Chemie International Edition,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 6, 2025
Z-DNA
binding
protein
1
(ZBP1)
has
emerged
as
a
critical
pathogen-sensing
that
upon
activation,
triggers
necroptotic
signaling
cascades,
leading
to
potent
inflammatory
response
and
potentially
causing
significant
tissue
damage.
However,
available
drugs
specifically
developed
for
the
effective
inhibition
or
degradation
of
ZBP1
is
still
lacking
so
far.
In
this
study,
we
covalent
recognition-based
PROTAC
(C-PROTAC)
molecule
ZBP1.
It
consists
DNA
aptamer
recognition
moiety
an
E3
enzyme-recruiting
unit,
connected
by
linker
containing
N-acyl-N-alkyl
sulfonamides
(NASA)
groups.
The
binds
ZBP1,
while
NASA-containing
facilitates
formation
bond
between
target
protein.
ligase-recruiting
unit
then
directs
ubiquitin-proteasome
system
degrade
ZBP1-PROTAC
complex.
This
approach
combines
high
specificity
aptamers
with
efficiency
degradation-inducing
capabilities
PROTACs,
providing
powerful
tool
targeted
degradation.
successful
application
technology
highlights
its
potential
selective
elimination
disease-associated
proteins
development
novel
therapeutic
strategies.
Angewandte Chemie,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 6, 2025
Abstract
Z‐DNA
binding
protein
1
(ZBP1)
has
emerged
as
a
critical
pathogen‐sensing
that
upon
activation,
triggers
necroptotic
signaling
cascades,
leading
to
potent
inflammatory
response
and
potentially
causing
significant
tissue
damage.
However,
available
drugs
specifically
developed
for
the
effective
inhibition
or
degradation
of
ZBP1
is
still
lacking
so
far.
In
this
study,
we
covalent
recognition‐based
PROTAC
(C‐PROTAC)
molecule
ZBP1.
It
consists
DNA
aptamer
recognition
moiety
an
E3
enzyme‐recruiting
unit,
connected
by
linker
containing
N
‐acyl‐
‐alkyl
sulfonamides
(NASA)
groups.
The
binds
ZBP1,
while
NASA‐containing
facilitates
formation
bond
between
target
protein.
ligase‐recruiting
unit
then
directs
ubiquitin‐proteasome
system
degrade
ZBP1‐PROTAC
complex.
This
approach
combines
high
specificity
aptamers
with
efficiency
degradation‐inducing
capabilities
PROTACs,
providing
powerful
tool
targeted
degradation.
successful
application
technology
highlights
its
potential
selective
elimination
disease‐associated
proteins
development
novel
therapeutic
strategies.
Metabolism,
Journal Year:
2025,
Volume and Issue:
unknown, P. 156258 - 156258
Published: April 1, 2025
More
and
more
steatotic
livers
undergo
resection
or
transplantation
but
they
exhibit
higher
susceptibility
to
ischemia-reperfusion
injury
(IRI),
which
results
in
increased
perioperative
complication
morbidity
mortality.
IRI
is
driven
by
various
cytokines
receptors,
both
of
are
extensively
modified
N-glycosylation.
We
aim
elucidate
from
the
perspective
Differentially
expressed
genes
glycoproteins
were
identified
with
RNA-seq
N-glycoproteomics.
Myeloid
LIF
hepatocyte
LIFR
knockout
mice
developed
examine
function
LIFR.
Modalities
including
phosphoproteomics,
ChIP-seq,
single
cell
RNA-seq,
metabolomics
immunoblotting
utilized
investigate
underlying
mechanisms.
transcription
myeloid
cells
N-glycosylation
hepatocytes
substantially
induced
normal
livers.
protected
through
activating
STAT3
promoting
downstream
TNFAIP3
expression,
was
facilitated
Mechanistically,
at
N238
stabilized
protein
disrupting
TRIM28-mediated
K48
ubiquitination
K254.
Furthermore,
N358/N658/N675
LIF/LIFR/gp130
complex
formation
subsequent
signal
transduction.
However,
livers,
partially
inhibited
due
hepatic
microenvironment
L-arginine
insufficiency,
while
defective
intracellular
UDP-GlcNAc
exhaustion.
Importantly,
combined
GlcNAc
treatment
reversed
expression
represents
potential
therapeutic
strategy
protect
insufficiency
aggravates
liver
IRI,
can
be
treatment.
Clinical and Translational Medicine,
Journal Year:
2025,
Volume and Issue:
15(5)
Published: April 27, 2025
Abstract
Background
Septic
cardiomyopathy
is
a
frequent
complication
in
patients
with
sepsis
and
associated
high
mortality
rate.
Given
its
clinical
significance,
understanding
the
precise
underlying
mechanism
of
great
value.
Methods
results
Our
unveiled
that
Z‐DNA
binding
protein
1
(ZBP1)
upregulated
myocardial
tissues
lipopolysaccharide
(LPS)‐treated
mice.
Single‐cell
mRNA
sequencing
(scRNA‐seq)
single‐nucleus
(snRNA‐seq)
indicated
Zbp1
endothelial
cells,
fibroblasts
macrophages
appeared
to
be
elevated
by
LPS,
which
partially
consistent
immunofluorescence.
Through
echocardiography,
we
identified
global
deletion
ZBP1
improves
cardiac
dysfunction
survival
rate
LPS‐treated
Mechanistically,
snRNA‐seq
showed
mainly
expressed
promotes
macrophage
polarisation
towards
M2‐subtype,
reduces
inflammatory
cell
infiltration.
Notably,
myeloid‐specific
deficiency
also
M2
dysfunction,
validating
role
macrophage‐derived
septic
dysfunction.
Finally,
revealed
LPS
increases
transcription
expression
through
signal
transducer
activator
(STAT1).
Fludarabine,
inhibitor
STAT1,
could
promote
improve
Conclusions
study
provides
evidence
novel
STAT1‐ZBP1
axis
promoting
cardiomyopathy,
underscores
potential
as
therapeutic
target
for
cardiomyopathy.
Key
points
Macrophage‐derivedZBP1
exacerbates
LPS‐induced
cellinfiltration.
Deletionof
from
M1
M2.
STAT1‐ZBP1axis
ZBP1has
emerged
inflammationand
