Signal Transduction and Targeted Therapy,
Journal Year:
2024,
Volume and Issue:
9(1)
Published: Jan. 8, 2024
Proprotein
convertase
subtilisin/kexin
type
9
(PCSK9)
has
evolved
as
a
pivotal
enzyme
in
lipid
metabolism
and
revolutionary
therapeutic
target
for
hypercholesterolemia
its
related
cardiovascular
diseases
(CVD).
This
comprehensive
review
delineates
the
intricate
roles
wide-ranging
implications
of
PCSK9,
extending
beyond
CVD
to
emphasize
significance
diverse
physiological
pathological
states,
including
liver
diseases,
infectious
autoimmune
disorders,
notably,
cancer.
Our
exploration
offers
insights
into
interaction
between
PCSK9
low-density
lipoprotein
receptors
(LDLRs),
elucidating
substantial
impact
on
cholesterol
homeostasis
health.
It
also
details
evolution
PCSK9-targeted
therapies,
translating
foundational
bench
discoveries
bedside
applications
optimized
patient
care.
The
advent
clinical
approval
innovative
inhibitory
therapies
(PCSK9-iTs),
three
monoclonal
antibodies
(Evolocumab,
Alirocumab,
Tafolecimab)
one
small
interfering
RNA
(siRNA,
Inclisiran),
have
marked
significant
breakthrough
medicine.
These
demonstrated
unparalleled
efficacy
mitigating
hypercholesterolemia,
reducing
risks,
showcased
profound
value
applications,
offering
novel
avenues
promising
future
personalized
medicine
disorders.
Furthermore,
emerging
research,
inclusive
our
findings,
unveils
PCSK9's
potential
role
indicator
cancer
prognosis
prospective
application
transformative
treatment.
highlights
aberrant
expression
various
forms,
association
with
prognosis,
crucial
carcinogenesis
immunity.
In
conclusion,
this
synthesized
integrates
existing
knowledge
providing
holistic
perspective
reshaping
paradigms
across
emphasizes
effect
PCSK9-iT,
underscoring
advancing
landscape
biomedical
research
capabilities
heralding
new
eras
Pharmacology & Therapeutics,
Journal Year:
2023,
Volume and Issue:
249, P. 108480 - 108480
Published: June 17, 2023
Lowering
blood
cholesterol
levels
efficiently
reduces
the
risk
of
developing
atherosclerotic
cardiovascular
disease
(ASCVD),
including
coronary
artery
(CAD),
which
is
main
cause
death
worldwide.
CAD
caused
by
plaque
formation,
comprising
deposits
in
arteries.
Proprotein
convertase
subtilisin
kexin/type
9
(PCSK9)
was
discovered
early
2000s
and
later
identified
as
a
key
regulator
metabolism.
PCSK9
induces
lysosomal
degradation
low-density
lipoprotein
(LDL)
receptor
liver,
responsible
for
clearing
LDL-cholesterol
(LDL-C)
from
circulation.
Accordingly,
gain-of-function
mutations
are
causative
familial
hypercholesterolemia,
severe
condition
with
extremely
high
plasma
increased
ASCVD
risk,
whereas
loss-of-function
associated
very
low
LDL-C
protection
against
CAD.
Since
discovery
PCSK9,
extensive
investigations
targeting
therapies
have
been
performed.
The
combined
delineation
clear
biology,
genetic
variants,
crystal
structures
major
drivers
antagonistic
molecules.
Today,
two
antibody-based
inhibitors
successfully
progressed
to
clinical
application
shown
be
effective
reducing
mitigating
events,
myocardial
infarction,
stroke,
death,
without
any
adverse
effects.
A
third
siRNA-based
inhibitor
has
FDA-approved
but
awaits
outcome
data.
In
this
review,
we
outline
focusing
on
structure
nonsynonymous
reported
gene
elaborate
PCSK9-lowering
strategies
under
development.
Finally,
discuss
future
perspectives
inhibition
other
disorders
beyond
disease.
Hepatology,
Journal Year:
2023,
Volume and Issue:
78(6), P. 1828 - 1842
Published: Feb. 20, 2023
Background
&
Aims:
SLC25A47
was
initially
identified
as
a
mitochondrial
HCC-downregulated
carrier
protein,
but
its
physiological
functions
and
transport
substrates
are
unknown.
We
aimed
to
investigate
the
role
of
in
hepatic
metabolism.
Approach
Results:
In
treatment
hepatocytes
with
metformin,
we
found
that
metformin
can
transcriptionally
activate
expression
Slc25a47
,
which
is
required
for
AMP-activated
protein
kinase
α
(AMPKα)
phosphorylation.
-deficient
mice
had
increased
lipid
content,
triglycerides,
cholesterol
levels,
deficiency
suppressed
AMPKα
phosphorylation
led
an
accumulation
nuclear
SREBPs,
elevated
fatty
acid
biosynthetic
activities.
Conversely,
when
overexpressed
mouse
liver,
activated
resulted
inhibition
lipogenesis.
Moreover,
using
diethylnitrosamine-induced
HCC
model,
deletion
promoted
tumorigenesis
development
through
mammalian
target
rapamycin
cascade.
Employing
homology
modeling
virtual
screening
human
metabolome
database,
demonstrated
NAD
+
endogenous
substrate
SLC25A47,
activity
-dependent
sirtuin
3
declined
mice,
followed
by
inactivation
AMPKα.
Conclusions:
Our
findings
reveal
hepatocyte-specific
transporter,
one
pharmacological
targets
regulates
homeostasis
AMPKα,
may
serve
potential
drug
treating
NAFLD
HCC.
Cancers,
Journal Year:
2023,
Volume and Issue:
15(5), P. 1397 - 1397
Published: Feb. 22, 2023
Cancer
patients
treated
with
immune
checkpoint
inhibitors
(ICIs)
are
exposed
to
a
high
risk
of
atherosclerosis
and
cardiometabolic
diseases
due
systemic
inflammatory
conditions
immune-related
atheroma
destabilization.
Proprotein
convertase
subtilisin/kexin
type
9
(PCSK9)
is
key
protein
involved
in
metabolism
low-density
lipoprotein
(LDL)
cholesterol.
PCSK9
blocking
agents
clinically
available
involve
monoclonal
antibodies,
SiRNA
reduces
LDL
levels
high-risk
atherosclerotic
cardiovascular
disease
events
multiple
patient
cohorts.
Moreover,
induces
peripheral
tolerance
(inhibition
cancer
cell-
recognition),
cardiac
mitochondrial
metabolism,
enhances
cell
survival.
The
present
review
summarizes
the
potential
benefits
inhibition
through
selective
antibodies
siRNA
cancer,
especially
those
ICIs
therapies,
order
reduce
potentially
improve
ICIs-related
anticancer
functions.
Heart Failure Reviews,
Journal Year:
2024,
Volume and Issue:
29(5), P. 917 - 937
Published: June 18, 2024
Proprotein
convertase
subtilisin/kexin
type-9
(PCSK9)
is
a
protein
that
regulates
low-density
lipoprotein
(LDL)
cholesterol
metabolism
by
binding
to
the
hepatic
LDL
receptor
(LDLR),
ultimately
leading
its
lysosomal
degradation
and
an
increase
in
(LDLc)
levels.
Treatment
strategies
have
been
developed
based
on
blocking
PCSK9
with
specific
antibodies
(alirocumab,
evolocumab)
production
small
regulatory
RNA
(siRNA)
(inclisiran).
Clinical
trials
evaluating
these
drugs
confirmed
their
high
efficacy
reducing
serum
LDLc
levels
improving
prognosis
patients
atherosclerotic
cardiovascular
diseases.
Most
studies
focused
action
of
LDLRs
subsequent
concentrations.
Increasing
evidence
suggests
adverse
effects
PCSK9,
particularly
vascular
wall,
may
also
result
from
mechanisms
independent
lipid
metabolism.
induces
expression
pro-inflammatory
cytokines
contributing
inflammation
within
wall
promotes
apoptosis,
pyroptosis,
ferroptosis
cardiomyocytes
thus
involved
development
progression
heart
failure.
The
elimination
may,
therefore,
not
only
be
treatment
for
hypercholesterolaemia
but
atherosclerosis
other
system
are
yet
fully
understood.
This
article
reviews
current
understanding
contribution
Knowledge
contribute
wider
use
inhibitors
Lipids in Health and Disease,
Journal Year:
2025,
Volume and Issue:
24(1)
Published: Feb. 21, 2025
Lipid
metabolism
is
a
well-regulated
process
essential
for
maintaining
cellular
functions
and
energy
homeostasis.
Dysregulation
of
lipid
associated
with
various
conditions,
including
cardiovascular
diseases,
neurodegenerative
disorders,
metabolic
syndromes.
This
review
explores
the
mechanisms
underlying
metabolism,
emphasizing
roles
key
species
such
as
triglycerides,
phospholipids,
sphingolipids,
sterols
in
physiology
pathophysiology.
It
also
examines
genetic
environmental
factors
contributing
to
dysregulation
challenges
diagnosing
managing
lipid-related
disorders.
Recent
advancements
lipid-lowering
therapies,
PCSK9
inhibitors,
ezetimibe,
bempedoic
acid,
olpasiran,
provide
promising
treatment
options.
However,
these
are
accompanied
by
related
cost,
accessibility,
patient
adherence.
The
highlights
need
personalized
medicine
approaches
address
interplay
between
genetics
metabolism.
As
lipidomics
advanced
diagnostic
tools
continue
progress,
deeper
understanding
disorders
could
pave
way
more
effective
therapeutic
strategies.
