Resveratrol alleviates testicular toxicity induced by anti-PD-1 through regulating the NRF2-SLC7A11-GPX4 pathway
Abstract
Background:
Fertility
preservation
is
a
critical
concern
for
reproductive-age
cancer
survivors,
as
conventional
cytotoxic
therapies
can
cause
irreversible
damage
to
the
reproductive
system,
potentially
depriving
them
of
ability
have
children
in
future.
Immune
checkpoint
inhibitors
(ICIs),
including
anti-programmed
cell
death
protein
1
(anti-PD-1),
become
standard
therapeutic
approach
various
malignancies.
However,
impact
ICIs
on
function
and
fertility
not
well
understood
remains
largely
unexplored
domain.
Methods:
Male
C57BL6/J
mice
with
B16
melanoma
were
assigned
into
four
groups:
control
,
anti-PD-1
(ICI)
RSV,
RSV
(ICI/RSV)
group.
ICI/RSV
groups
received
(40
mg/kg)
orally
every
other
day
one
month,
while
controls
vehicle.
ICI
injected
antibody
(10
weekly,
IgG2b
kappa
antibody.
Parameters
like
body
testicular
weight,
sperm
concentration,
Western
blotting
ferroptosis
markers
measured.
Furthermore,
oxidative
stress
biomarkers,
lipid
oxidation
factors,
gonadal
hormone
levels
quantified
using
commercial
kits.
Results:
Anti-PD-1
therapy
caused
male
dysfunction,
evidenced
by
reduced
altered
levels,
disruption
blood-testis
barrier
(BTB)
integrity.
was
key
mechanism
anti-PD-1-induced
characterized
disrupted
iron
homeostasis,
elevated
peroxidation,
suppression
system
Xc−/glutathione
peroxidase
4
(GPX4)
axis.
Additionally,
therapy
diminished
antioxidant
defenses
inhibiting
nuclear
factor
erythroid
2-related
2
(NRF2)
pathway,
thereby
increasing
susceptibility
ferroptosis.
Crucially,
treatment
ameliorated
dysfunction.
This
achieved
reducing
T
infiltration,
lowering
interferon-gamma
activating
NRF2
maintainingiron
homeostasis.
Conclusions:
Our
study
demonstrates
that
anti-PD-1triggers
testis,
causing
Resveratrol
may
offer
protection
against
toxicity
associated
anti-PD-1,
particularly
through
its
anti-ferroptosis
properties.
Research Square (Research Square), Год журнала: 2024, Номер unknown
Опубликована: Ноя. 4, 2024
Язык: Английский