Molecular Medicine,
Journal Year:
2025,
Volume and Issue:
31(1)
Published: April 24, 2025
Abstract
Background
The
dysregulation
of
neuroinflammation
triggered
by
imbalance
microglia
M1/M2
polarization
is
a
key
pathogenic
factor
and
closely
associated
with
occurrence
depression.
Formononetin
(FMN),
natural
non-steroidal
isoflavonoid,
has
been
confirmed
to
exhibit
remarkable
anti-inflammatory
efficacy,
but
the
impact
FMN
on
depression
underlying
antidepressant
mechanisms
are
still
not
fully
understood.
This
study
aimed
investigate
whether
effect
involved
in
modulating
polarization,
if
so,
what
mechanisms.
Methods
Lipopolysaccharide
(LPS)-induced
depressive
mice
were
used
FMN.
Microglia
cell
line
BV2
stimulated
LPS
was
employed
pharmacological
Effects
neuronal
damage
detected
H&E,
Nissl
Golgi
staining.
efficacy
evaluated
immunostaining
western
blots
vivo
vitro
.
In
addition,
molecular
docking,
luciferase
reporter
assay,
cellular
thermal
shift
assay
(CETSA)
drug
affinity
responsive
target
stability
(DARTS)
confirm
direct
Results
Our
results
showed
that
significantly
reverses
depression-like
behaviors,
alleviates
damage,
rebalances
inhibits
NLRP3
inflammasome
enhances
microglial
autophagy
level
prefrontal
cortex
LPS-induced
mice.
assays,
unraveled
inhibitor
chloroquine
(CQ)
blocks
effects
inhibiting
rebalancing
polarization.
Moreover,
PPARα
identified
as
can
activate
PPARα-mediated
autophagy.
Furtherly,
combination
agonist
(WY14643)
had
no
significant
additive
whereas
antagonist
(GW6471)
abrogated
these
pharmacologic
BV2.
Importantly,
GW6471
exhibited
similar
abolish
Conclusion
firstly
demonstrated
rebalance
inhibit
inflammasome,
involvement
activating
ameliorate
which
provides
novel
view
elucidate
also
offers
potential
therapeutic
for
