Journal of Translational Medicine,
Год журнала:
2025,
Номер
23(1)
Опубликована: Март 25, 2025
Metabolic
dysfunction-associated
steatotic
liver
disease
(MASLD)
is
the
most
common
chronic
worldwide,
with
a
prevalence
as
high
32.4%.
MASLD
encompasses
spectrum
of
pathologies,
ranging
from
steatosis
to
metabolic
steatohepatitis
(MASH),
fibrosis,
and,
in
some
cases,
progression
end-stage
(cirrhosis
and
hepatocellular
carcinoma).
A
comprehensive
understanding
pathogenesis
this
highly
prevalent
may
facilitate
identification
novel
targets
for
development
improved
therapies.
E3
ubiquitin
ligases
deubiquitinases
(DUBs)
are
key
regulatory
components
ubiquitin‒proteasome
system
(UPS),
which
plays
pivotal
role
maintaining
intracellular
protein
homeostasis.
Emerging
evidence
implicates
that
aberrant
expression
DUBs
involved
MASLD.
Here,
we
review
abnormalities
by
(1)
discussing
their
targets,
mechanisms,
functions
MASLD;
(2)
summarizing
pharmacological
interventions
targeting
these
enzymes
preclinical
clinical
studies;
(3)
addressing
challenges
future
therapeutic
strategies.
This
synthesizes
current
highlight
strategies
based
on
UPS
progressive
disease.
Frontiers in Psychiatry,
Год журнала:
2024,
Номер
15
Опубликована: Авг. 23, 2024
Background
The
incidence
rate
of
adolescent
depression
and
anxiety
has
been
increasing
since
the
outbreak
COVID-19,
which
there
are
no
effective
therapeutic
drugs
available.
Si-ni
San
is
commonly
used
in
traditional
Chinese
medicine
for
treatment
depression-like
as
well
anxiety-like
behavior,
but
its
mechanism
treating
combined
with
during
adolescence
not
yet
clear.
Methods
Network
pharmacology
was
to
explore
potential
drug
molecules
related
targets,
molecular
docking
dynamics
(MD)
simulation
were
evaluate
interaction
between
a
model
rats
following
behavioral
tests
biology
verify
results
from
network
docking.
Results
As
result,
256
active
ingredients
1128
targets
screened
out.
Among
them,
quercetin,
Luteolin,
kaempferol,
7-Methoxy-2-methyl
isoflavone,
formononetin
showed
be
most
ingredients;
while
STAT3,
IL6,
TNF,
AKT1,
TP53,
IL1B,
MAPK3,
VEGFA,
CASP3,
MMP9
targets.
AGE-RAGE
signaling
pathway
diabetic
complications,
IL-17
pathway,
HIF-1
PI3K-Akt
TNF
involved
anti-inflammation
processes,
probable
pathways
regulated
by
San.
Molecular
MD
compounds
inflammation-associated
revealed
good
binding
abilities
nobiletin
PTGS2
PPARγ.
In
experiment
rats,
markedly
suppressed
early
maternal
separation
(MS)
chronic
unpredictable
mild
stress
(CUMS)-induced
anxiety.
qPCR
further
indicated
that
oxidative
inflammatory
response.
Conclusion
This
study
demonstrates
anxiety-
behavior
induced
MS
CUMS
can
ameliorated
improved
inflammation
hippocampus
via
targeting
Nrf2
helping
reveal
Frontiers in Pharmacology,
Год журнала:
2025,
Номер
15
Опубликована: Янв. 15, 2025
TRIB3
has
been
reported
to
mediate
breast
cancer
(BC)
proliferation
and
metastasis
by
interacting
with
AKT1,
blocking
the
interaction
between
AKT1
can
inhibit
progression
of
BC.
Besides,
inhibiting
turn
"cold
tumor"
hot
also
proved
be
an
effective
therapeutic
strategy
for
Thus,
this
study
aim
find
drugs
that
bind
BC
progression,
further
elucidate
its
mechanism.
The
possible
inhibitors
were
screened
high-throughput
molecular
docking,
CETSA,
CO-IP
assay.
Then,
effect
inhibitor
anti
was
assessed
CCK-8
assay,
flow
cytometry,
plate
colony
formation
transwell
assay;
RNA-seq
empolyed
potential
mechanism
Parishin
B
(PB)
anti-BC.
Finally,
on
lung
in
vivo
evaluated.
PB
as
a
TRIB3,
CETSA
assay
indicated
could
target
block
TRIB3-AKT1
interaction.
In
addition,
exhibited
good
anti-BC
activity
without
drug
toxicity
normal
cells
experiments
vitro,
analysis
suggested
invasion
related
cell
cycle.
It
vivo.
demonstrated
regulating
cycle,
providing
agent
treatment
Advanced Science,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 15, 2025
Abstract
The
global
incidence
of
Metabolic
dysfunction‐associated
steatohepatitis
(MASH)
is
increasing,
highlighting
the
urgent
need
for
new
treatment
strategies.
This
study
aimed
to
investigate
involvement
tripartite
motif‐containing
25
(TRIM25)
in
MASH
progression
and
explore
therapeutic
potential
TRIM25
inhibitor,
C
27
H
26
N
2
O
4
S.
Functional
studies
reveal
that
promoted
lipid
accumulation
inflammation
by
ubiquitinating
degrading
insulin‐induced
gene
1
(INSIG1),
thereby
enhancing
nuclear
translocation
sterol
regulatory
element‐binding
protein
(SREBP2)
upregulating
biosynthesis
genes.
In
vivo
experiments
using
knockout
mice
demonstrated
deletion
ameliorated
progression,
reduced
fibrosis,
decreased
inflammatory
cell
infiltration.
It
identifies
S
as
a
specific
inhibitor
TRIM25.
effectively
INSIG1
ubiquitination
attenuated
hepatocytes.
To
enhance
hepatic
delivery
S,
it
utilizes
exosomes
derived
from
stellate
cells
(HSC‐EVs).
Biodistribution
analysis
confirmed
HSC‐EVs
preferentially
accumulated
liver.
mouse
model,
HSC‐EV‐encapsulated
(C
S@HSC‐EV)
significantly
alleviated
severity
fibrosis.
highlights
critical
role
presents
S@HSC‐EV
promising
approach
treatment.
Journal of Lipid Research,
Год журнала:
2025,
Номер
unknown, С. 100835 - 100835
Опубликована: Май 1, 2025
Metabolic
dysfunction-associated
steatohepatitis
(MASH)
has
become
global
health
challenges
with
limited
therapeutic
strategy.
Here,
the
present
study
aims
to
identify
promising
drug
candidates
for
MASH
and
clarify
their
pharmacological
mechanism.
By
an
extensive
screening
of
FDA-approved
hepatoprotective
medicines
using
a
PA/OA-stimulated
hepatocytes
model,
we
identified
daclatasvir
showing
potent
anti-MASH
capacity
against
hepatic
steatosis
deposition
inflammatory
response.
The
benefits
was
further
validated
in
mouse
models,
induced
by
high-fat
high-cholesterol
(HFHC)
diet
16
weeks
or
methionine-choline-deficient
(MCD)
4
weeks,
as
supported
markedly
improved
histopathological
characteristics,
serum
biochemical
level,
transcriptomic
analyses.
Using
molecular
docking
assay
followed
isothermal
titration
calorimetry
confirmation,
that
functions
new
perilipin-2
(PLIN2)
inhibitor
interrupting
its
stability.
In
specific,
PLIN2
subjected
MARCH6-mediated
protein
degradation
K11-type
ubiquitination.
Daclatasvir
can
directly
bind
enhance
interaction
MARCH6,
leading
strengthened
ubiquitinational
subsequent
decline
lipid
droplet
disintegration
lipotoxicity.
specific
mutation
at
binding
amino
acid
sites
largely
abolished
benefit
daclatasvir.
conclusion,
findings
our
first
time
anti-HCV
novel
degradant
protection.
