Diabetes mellitus (DM) is the most common chronic
metabolic disease worldwide, with its global incidence and
prevalence rising continuously over the past 30 years: The number
of adults living with diabetes has quadrupled from 198 million in
1990 to 828 million in 2022, and the age-standardized prevalence
has doubled from 7.0 to 14.0%, with sustained growth observed in
the vast majority of countries worldwide (1,2).
Clinically, complications of DM mainly include coronary heart
disease, peripheral artery disease, retinopathy, neuropathy and
nephropathy (3). In recent
years, the incidence of diabetic nephropathy (DN), a serious kidney
disease, has continued to rise, 20 to 40% of patients with diabetes
may develop kidney disease (4).
Long-term hyperglycemia can alter the physiological
microenvironment, triggering reactions such as oxidative stress
(OS), pyroptosis, immune responses, mitochondrial dysfunction and
lysosomal damage. These reactions can cause a series of abnormal
adaptations, including glomerular hypertrophy, podocyte loss and
mesangial matrix dilation. In the development of DN, activation of
the NOD-like Receptor family Pyrin domain containing 3 (NLRP3)
inflammasomes is a key contributory factor in a variety of renal
injury mechanisms (5,6).
The NLRP3 inflammasome is an essential intracellular
multiprotein complex in innate immunity, predominantly expressed in
the cytoplasm of innate immune cells such as macrophages, dendritic
cells and mast cells, and is currently the most well-established
inflammasome complex (7). The
NLRP3 inflammasome recognizes multiple pathogen molecular patterns
and endogenous danger signals, recruits and activates caspase-1 via
the apoptosis-associated speck-like protein (ASC) aptamer, induces
cleavage of downstream Gasdermin D (GSDMD) and regulates the
release of IL-1β and IL-18, ultimately leading to pyroptosis
(8). The NLRP3 inflammasome can
be activated not only by various pathogenic and environmental
stimuli, such as microbial cell wall components, nucleic acids and
alum and silica, but also by endogenous hazard signals, such as
lipopolysaccharides, adenosine triphosphate, hyaluronic acid, islet
amyloid polypeptide, heme, oxidized mitochondrial DNA and the
membrane attack complex (MAC) (9,10). In autoimmune diseases,
arteriosclerosis and diabetic complications, abnormal activation of
the NLRP3 inflammasome can trigger excessive inflammatory
responses, acts as one of the key inflammatory mediators, rather
than a sole dominant driver of tissue damage (11-13).
In the progression of DN, alterations in the renal
microenvironment lead to excessive activation of NLRP3
inflammasomes, which trigger apoptosis and pyroptosis in glomerular
mesangial cells, endothelial cells and tubular epithelial cells,
ultimately resulting in chronic inflammation and renal fibrosis
(14,15). Targeted inhibition of
NLRP3-mediated pyroptosis is considered to be a potential
therapeutic approach (16);
NLRP3 knockout in diabetic mice was shown to alleviate
streptozotocin-induced glomerular hypertrophy, glomerular sclerosis
and mesangial matrix dilation (17). The present review introduces the
structure and function of the NLRP3 inflammasome and examines the
various pathways involved in its activation. The potential roles
and mechanisms of the NLRP3 inflammasome in DN are discussed and
finally, current therapeutic strategies targeting the NLRP3
inflammasome for the treatment of DN are summarized.
DN is a specific form of kidney injury and the
leading cause of end-stage kidney disease (18). The chronic renal failure
resulting from DN is also a major cause of mortality among patients
with DM (19,20). DN involves both structural
changes in the kidneys and changes in kidney function (21). Structurally, DN includes
glomerular mesangial dilation, thickening of the basement membrane,
podocyte reduction, nodular glomerulosclerosis and endothelial cell
destruction (22,23). Functionally, DN is characterized
by increased albumin excretion and impaired glomerular filtration
(24). In addition, a key
pathogenic factor for the development of DN is persistent
hyperglycemia and it has been shown to induce marked renal
structural damage through advanced glycation end-product (AGE)
accumulation, activation of the polyol and hexosamine pathways,
stimulation of the renin-angiotensin-aldosterone and sympathetic
nervous systems, and the onset of insulin resistance and
endothelial dysfunction (25,26). Studies have shown that factors
such as OS, immune response, mitochondrial damage, pyroptosis and
podocyte autophagy can all cause damage to these cells (27,28), which disrupts the filtration
barrier and leads to elevated proteinuria, abnormal glomerular
filtration rate and elevated creatinine levels (29,30), thereby promoting the occurrence
and development of DN (Fig. 1).
During the development the DN, all of these factors trigger an
inflammatory response, the core of which is the inflammasome. This
cytoplasmic multiprotein complex activates the inflammatory protein
caspase-1 and serves a key role in the innate immune system
(31). The NLRP3 inflammasome,
as a key participant, is widely involved in the inflammatory
response by forming and releasing inflammatory cytokines, thereby
exacerbating the development of DN (32,33).
Inflammasomes are large multiprotein complexes
belonging to the pattern recognition receptor (PRR) family and
serve a key role in the innate immune system (34). They are composed of inflammatory
caspases and various sensors, including the nucleotide-binding
domain and leucine-rich repeat-containing receptors (NLRs) family,
pyrin and absent in melanoma 2 (AIM2) (35,36). Members of the NLR family
typically contain three conserved structural domains: A C-terminal
leucine-rich repeat (LRR) region, a central nucleotide-binding site
and an NACHT domain responsible for oligomerization and an
N-terminal effector domain (37,38). The NLR comprises several members,
including NLRP1, NLRP3, NLRP6 and NLRC4, among which the NLRP3
inflammasome is the most well-characterized (39,40).
The NLRP3 inflammasome is composed of NLRP3, a
multiprotein complex consisting of ASC and caspase-1 (41). This complex serves a key role in
the immune system, recognizing pathogen-associated molecular
patterns (PAMPs) and damage-associated molecular patterns (DAMPs)
to initiate immune responses (42). Upon activation, the NLRP3
inflammasome recruits ASC to form speck-like aggregates, which
facilitate the conversion of pro-caspase-1 into its active p10/p20
subunits (43). Activated
caspase-1 subsequently processes the inactive precursors pro-IL-1
and pro-IL-18 into their mature, bioactive forms, thereby promoting
the secretion of these key pro-inflammatory cytokines. Furthermore,
caspase-1 cleaves the pyroptosis executioner protein GSDMD into its
N- and C-terminal fragments, leading to membrane pore formation,
cellular lysis and pyroptotic cell death (44,45).
NLRP3 functions as a pivotal sensor in sterile
inflammatory signaling and acts as a central regulator of chronic
inflammatory disorders. Under homeostatic conditions, the NLRP3
inflammasome exerts beneficial effects by facilitating pathogen
clearance, promoting tissue repair and preserving physiological
balance. By contrast, its aberrant or sustained activation drives
chronic inflammation and tissue damage (Table I) (59-87).
Pyroptosis of inflammatory and renal intrinsic cells
mediated by the NLRP3 inflammasome is a key contributory cell death
mode in renal inflammation and injury during DN. The canonical
NLRP3 inflammasome-mediated pyroptosis pathway is the predominant
pathway in DN, with considerable in vivo evidence, while the
non-canonical (caspases-4/5/11-mediated) and
caspase-3/GSDME-mediated pathways have presently been only
validated in vitro and lack direct in vivo
verification in DN models. The pyroptosis pathway is characterized
by the formation of pores in the cell membrane, leading to cell
rupture and the release of pro-inflammatory factors, exacerbating
renal inflammation and fibrosis (88). This process is initiated by
stimuli including hyperglycemia, OS, AGEs and lipotoxicity, in
which activation of the NLRP3 inflammasome represents a pivotal
event (89). Following NLRP3
inflammasome activation, Caspase-1 cleaves GSDMD and
pro-IL-1β/IL-18, leading to the release of inflammatory mediators
and the induction of pyroptosis (90).
In the atypical inflammasome pathway, caspases-4, -5
and -11 directly detect pathogen molecules via their caspase
recruitment domains (CARDs), leading to caspase-1 activation, IL-1
and IL-18 maturation, GSDMD cleavage and IL-1 release (95,96). GSDMB does not induce pyroptosis
via its N-terminal domain, as other Gasdermin family members do,
but instead promotes caspase-4 activity by directly binding to the
caspase-4 CARD domain (97).
Subsequently, activated caspase-4 can form membrane pores via GSDMD
activity and potassium influx can activate NLRP3. Another study
demonstrated that the downregulation of caspase-4 inhibits
TNF-α-induced pyroptosis in human pulmonary artery endothelial
cells, as well as the activation of GSDMD and GSDME (98). Furthermore, caspase-11 recognizes
its substrates, predominantly GSDMD, via the P1'-P4' region of the
target protein (99,100).
Finally, the caspase-3-mediated inflammasome pathway
is also associated with pyroptosis as caspase-3 is activated during
LPS-induced pyroptosis (101).
GSDME can also be cleaved by caspase-3, leading to a transition
from apoptosis to pyroptosis (102). When NLRP3-specific inhibitors
were used to suppress NLRP3-mediated pyroptosis, ATP induced
pyroptosis in macrophages via the caspase-3/GSDME axis (103). Meanwhile, activated caspase-3
also inactivates the pore-forming domain of GSDMD, which inhibits
GSDMD-mediated pyroptosis (104). Notably, both GSDMD-NT
(N-terminal) and GSDME-NT can act on mitochondria, leading to
increased ROS production, inducing apoptosis, further stimulating
the release of inflammatory substances and exacerbating tissue
damage (105,106). Notably, the non-canonical
inflammasome pathway and caspase-3/GSDME-mediated pyroptosis
pathway have not been validated using in vivo DN models,
whereas the canonical NLRP3/caspase-1/GSDMD pathway is fully
supported by multiple genetic and pharmacological in vivo
studies (88,90,107).
The progression of DN is associated with pyroptosis,
which is regulated by five interacting hierarchical core signaling
pathways (NF-κB/NLRP3, TXNIP/NLRP3, Nrf2/HO-1/NLRP3, HIF-1α/NLRP3
and PTEN/PI3K/Akt) (TXNIP, thioredoxin-interacting protein; Nrf2,
nuclear factor erythroid 2-related Factor 2; HO-1, heme
oxygenase-1; HIF-1α, hypoxia-inducible factor-1α) rather than
independent mechanisms (Fig. 4).
These pathways form an upstream-downstream regulatory hierarchy
with extensive crosstalk and are divided into three modules: NF-κB
acts as the top upstream module, priming NLRP3 inflammasome by
transcriptionally upregulating NLRP3, pro-IL-1, pro-IL-18, and
activating TXNIP/HIF-1α; the midstream module (TXNIP/NLRP3,
Nrf2/HO-1/NLRP3, HIF-1/NLRP3) mediates NLRP3 activation (TXNIP
binds NLRP3 via ROS, Nrf2/HO-1 negatively regulates ROS/TXNIP/NF-κB
but is impaired in DN and HIF-1α forms a positive feedback loop);
the PTEN/PI3K/Akt pathway serves as the final facilitator, as
hyperglycemia inactivates PTEN to hyperactivate Akt, amplifying the
cascade and promoting NLRP3-ASC-caspase-1 assembly (108-110). Collectively, these pathways
converge to three core nodes (NF-κB-mediated priming,
ROS-TXNIP-induced NLRP3 oligomerization and Akt-mediated execution)
to drive aberrant NLRP3 activation and pyroptosis in DN, indicating
multi-pathway synergistic targeting as a rational therapeutic
strategy.
OS refers to a pathological state in which the
generation rate of ROS and reactive nitrogen species (RNS) in the
body exceeds the clearance capacity of the endogenous antioxidant
system, resulting in an imbalance in oxidative and antioxidant
homeostasis (111). OS in DN is
predominantly caused by the overproduction of ROS and RNS, induced
by factors such as hyperglycemia and AGEs (112). A previous study has shown that
hyperglycemia can induce OS and podocyte damage by mediating the
Von Hippel-Lindau E3 ubiquitin ligase, which promotes the
ubiquitin-mediated degradation of glucose-6-phosphate dehydrogenase
(113). Advanced oxidation
protein products (AOPPs) are oxidation-modified products formed
after plasma proteins are attacked by ROS (114); AOPPs can synergize with AGEs to
activate NADPH oxidase (NOX), leading to excessive ROS production
and NF-κB activation, thereby triggering the Wnt/β-catenin
signaling pathway and ultimately mediating podocyte
dedifferentiation and epithelial-mesenchymal transition (EMT)
(115). This oxidative
imbalance mediates kidney injury through multiple pathways,
including glomerular endothelial cell damage, mesangial cell
proliferation, increased extracellular matrix (ECM) deposition,
induction of podocyte apoptosis, suppression of podocyte protein
expression, EMT-related pathological changes, inflammatory
factor-driven injury, renal vascular endothelial cell impairment
and mitochondrial dysfunction (116).
In the pathological progression of DN, the NLRP3
inflammasome serves a pivotal role by driving the
OS-inflammation-cell injury cascade. Under hyperglycemic
conditions, aberrant NOX activation and dysfunction of the
mitochondrial electron transport chain in renal tissues lead to
excessive ROS production, which acts as a key initiating signal for
NLRP3 inflammasome activation (117-119).
ROS can induce NLRP3 oligomerization through
multiple mechanisms. First, ROS directly oxidize TXNIP, promoting
its binding to NLRP3 and thereby relieving Trx-mediated inhibition
of NLRP3 (120). Second, ROS
disrupt lysosomal membrane stability, leading to the release of
cathepsin B and subsequent proteolytic signaling (121). Third, ROS trigger the release
of mitochondrial (mt) DNA and the accumulation of mtROS, which
activate innate immune responses through DAMPs (122). After NLRP3 activation, ASC is
recruited and caspase-1 is cleaved, promoting the conversion of
IL-1β and IL-18 precursors into mature inflammatory factors
(123). IL-1β activates the
NF-κB pathway in renal interstitial fibroblasts, induces expression
of monocyte chemoattractant protein-1 (MCP-1) and intercellular
adhesion molecule-1 (ICAM-1), which exacerbates macrophage
infiltration and renal interstitial fibrosis. IL-18, together with
IFN-γ, promotes M1-type polarization in renal tubular epithelial
cells and amplifies the local inflammatory response (124-126). Meanwhile, caspase-1-mediated
cleavage of GSDMD forms pore-forming proteins, causing pyroptosis
in podocytes and renal tubular epithelial cells, disrupting the
glomerular filtration barrier and inducing tubulointerstitial
injury (127,128). Notably, inflammatory factors
form a positive feedback loop with OS signaling. IL-1β and TNF-α
enhance ROS production by upregulating NOX subunits, while ROS
further amplify the inflammatory cascade by activating NLRP3. This
cycle ultimately contributes to mesangial matrix expansion,
basement membrane thickening and tubular atrophy, thereby
accelerating the progression of DN (129,130). OS-driven NLRP3 inflammasome
abnormal activation not only serves as the core hub of DN
inflammatory damage, but also acts as a key molecular node
connecting glycolipid metabolism disorder and renal tissue fibrosis
(Fig. 5).
Mitochondria, as the prominent energy-metabolism
organelles within cells, play an indispensable role in aerobic
respiration (131). Podocytes
are rich in mitochondria, which are decisive for the normal
physiological function and energy supply of podocytes (132). In the pathological process of
DN, mitochondrial dysfunction is considered a key mechanism of
podocyte damage, involving abnormalities in oxidative
phosphorylation (OXPHOS), dysregulation of mitochondrial dynamics,
defects in biosynthesis, dysregulation of autophagy and
interactions among multiple signaling pathways (133-135). Hyperglycemia promotes the
formation of AGEs from glucose, which then bind to RAGE on the
surface of renal cells, generating a large amount of ROS via NOX.
ROS can directly attack mitochondria, disrupt mitochondrial
membrane structure, activate MAPK pathway, phosphorylate the
subunit of the mitochondrial respiratory chain complex and inhibit
OXPHOS efficiency. Furthermore, this downregulates the expression
of mitochondrial antioxidant enzymes, weakens the clearance ability
of mtROS and intensifies OS (136,137). The novel molecular mechanism by
which mitochondrial damage activates the NLRP3 inflammasome mainly
involves the regulatory role of mitochondrial metabolites and the
participation and synergy of the cGAS-STING pathway (138). It first manifests as the dual
effects of succinic acid; under hyperglycemic conditions, the
mitochondrial tricarboxylic acid cycle becomes impaired, leading to
succinic acid accumulation. Whilst excess succinic acid upregulates
NLRP3 transcription by stabilizing HIF-1α, it also inhibits
mitochondrial succinate dehydrogenase, which promotes electron
leakage from the electron transport chain and enhances mtROS
production. Together, this creates a positive feedback loop
(139). A further mechanism of
action is the mitochondrial targeting effect of ceramides, with
ceramide synthase 6 catalyzing mitochondrial ceramides, which leads
to mtDNA release and NLRP3 activation (140). In addition,
hyperglycemia-induced enhanced glycolysis leads to intracellular
lactic acid accumulation. Lactic acid directly binds to the NLRP3
promoter region by modifying histone H3 lysine 18 to promote its
transcriptional activation (141). Regarding the cGAS-STING
pathway, hyperglycemia-induced mitochondrial damage leads to mtDNA
leakage into the cytoplasm; cGAS recognizes mtDNA to generate
cGAMP, which activates STING and recruits TBK1, which
phosphorylates IRF3 and NF-κB to promote the expression of
pro-inflammatory factors such as Interferon-beta (IFN-β), IL-6 and
TNF-α. At the same time, the cGAS-STING pathway can act
synergistically with NLRP3 by upregulating NLRP3 transcription and
enhancing mtROS production, thereby facilitating inflammasome
assembly and further exacerbating the progression of DN (Fig. 6) (142,143).
The immune-mediated damage of DN centers on the
overactivation of innate immune pathways, which work in synergy to
drive the inflammatory cascade and fibrosis in the kidneys
(144). The initial triggers of
injury include hyperglycemia, glycotoxicity, AGEs and OS, all of
which cause cellular damage and lead to the release of DAMPs and
mtDNA. These danger signals subsequently activate TLRs (such as
TLR2 or TLR4) and the NLRP3 inflammasome (145,146). TLR signaling induces the
expression of pro-inflammatory cytokines (such as IL-6 and TNF-α)
and ICAM-1 through the NF-κB pathway, which promotes the
infiltration of macrophages and T cells. Meanwhile, the NLRP3
inflammasome mediates the maturation and release of IL-1β and IL-18
via caspase-1, amplifying the inflammatory response and triggering
podocyte apoptosis (147,148). In terms of immune cell effects,
macrophages recruit and release fibrotic factors through CCL2-CCR2
signaling, and T cells enhance the inflammatory response through
IFN-γ, both of which form a pro-inflammatory and pro-fibrotic
positive feedback loop with innate cells (149,150). Ultimately, these immune
mechanisms lead to the thickening of the glomerular basement
membrane, mesangial dilation, interstitial fibrosis and loss of
podocytes, resulting in pathological features such as proteinuria
and a gradual decline in renal function, which in turn cause
glomerular sclerosis and tubulointerstitial fibrosis driven by
chronic inflammation, eventually developing into end-stage renal
disease (151,152).
In DN, the activation of NLRP3 inflammasomes drives
renal immunopathological damage through multiple mechanisms. The
core effect is the amplification of the inflammatory cascade. Upon
activation of the NLRP3/caspase-1 pathway, mature IL-1β and IL-18
are released through cleavage of their precursors, triggering
infiltration of immune cells such as macrophages and T cells into
the renal interstitium and inducing the secretion of chemokines
such as MCP-1 and IL-6, thereby forming a positive feedback
inflammatory loop. Additionally, IL-1β activates the MAC via the
classical complement pathway, directly damaging the glomerular
basement membrane (153-155).
At the level of intrinsic kidney cell damage, NLRP3 activation
results in the loss of podocyte slit diaphragm proteins and fusion
of podocyte foot processes, leading to proteinuria. NLRP3
activation also induces pyroptosis of renal tubular epithelial
cells through the CD36-mtROS-NLRP3 axis, releasing pro-inflammatory
contents. Simultaneously, NLRP3 activation promotes mesangial cell
proliferation and ECM secretion, accelerating glomerular sclerosis
(156-158). During fibrosis, IL-1β and IL-18
promote fibroblast activation and collagen deposition by
upregulating TGF-β, inducing EMT and causing mitochondrial
dysfunction through sustained mtROS production, which leads to
renal interstitial fibrosis and an irreversible decline in renal
function (159-161). The multifaceted effects of this
pathological network indicate that the NLRP3 inflammasome serves as
a central regulatory node for both immune-mediated injury and
fibrotic progression in DN (Fig.
7).
Autophagy is a highly conserved process in
eukaryotic cells, in which autophagosomes enclose damaged
organelles, misfolded proteins or pathogens and fuse with lysosomes
to degrade their contents (162). It is mainly classified into
three types based on substrate handling and function:
Macroautophagy, microautophagy and chaperone-mediated autophagy.
Podocyte autophagy is the process by which glomerular podocytes
selectively or non-selectively degrade damaged intracellular
components through pathways primarily mediated by macroautophagy,
and is supplemented by chaperone-mediated autophagy. This process
regulates cellular metabolism and stress responses, ultimately
preserving podocyte survival, structural integrity and filtration
function (163).
In DN, hyperglycemia directly inhibits podocyte
autophagy through three main mechanisms. First, DN activates
negative regulatory pathways of autophagy via the PI3K-AKT-mTOR and
PKC-mTOR pathways, where mTORC1 suppresses the assembly and
activation of the autophagy initiation complex, which blocks
autophagy initiation. Second, hyperglycemia-induced NF-κB
translocation into the nucleus allows NF-κB to bind the negative
regulatory element in the Beclin1 promoter, downregulating Beclin1
expression and activity and inhibiting autophagy nucleation.
Finally, excessive ROS and mtROS production damages lysosomal
membranes, resulting in lysosomal membrane permeabilization (LMP)
(164,165). LMP causes lysosomal hydrolases
to leak into the cytoplasm, degrading autophagy-related proteins,
blocking autophagosome degradation, disrupting autophagic flux and
leading to autophagosome accumulation (166). Blocked autophagy initiation,
defective nucleation and disrupted flux lead to a marked reduction
in podocyte autophagic activity, preventing effective clearance of
damaged intracellular components, particularly mitochondria. This
causes mitochondrial dysfunction, activates the NLRP3 inflammasome
and aggravates cellular injury (132,167).
The activation of the NLRP3 inflammasome involves
two stages, initiation and activation, followed by the subsequent
release of effector molecules. During the activation phase,
hyperglycemia and autophagy deficiency synergistically activate the
NF-κB pathway. Hyperglycemia triggers NF-κB through PKC-b2 and the
AGEs-RAGE pathway, with AGEs binding to RAGE to activate MAPK and
NF-κB, leading to phosphorylation and nuclear translocation of the
NF-κB subunit. At the same time, impaired autophagy causes
accumulation of mtROS from damaged mitochondria, which promotes
oxidative modification and ubiquitin-mediated degradation of IκBα
and further enhances NF-κB activity (168,169). Activated NF-κB binds to the κB
binding site in the promoter region of NLRP3, pro-IL-1β and
pro-IL-18 genes after entering the nucleus, which markedly
upregulates their mRNA transcription and protein expression levels,
thus providing the necessary components for inflammasome assembly
(170). Mitochondrial
dysfunction caused by autophagy defects leads to the release of
multiple DAMPs in the activation phase. mtROS oxidize cysteine
residues in NLRP3, which alters the conformation of NLRP3 and
converts it into an active state. The loss of the mitochondrial
outer membrane potential triggers the opening of the mitochondrial
permeability transition pore, causing mtDNA to leak into the
cytoplasm, where it either directly binds to the LRR domain of
NLRP3 or indirectly promotes NLRP3 oligomerization via the
cGAS-STING pathway. Once activated, NLRP3 oligomerizes through the
NACHT domain, recruits the adaptor protein ASC via the CARD domain,
and induces ASC self-polymerization through the PYD domain to form
the ASC speck, which subsequently recruits pro-caspase-1 and drives
its autocatalytic activation (171,172). In the effector molecule release
phase, activated caspase-1 generates mature cytokines by
specifically cleaving pro-IL-1β and pro-IL-18. At the same time,
caspase-1 cleaves the pyroptosis effector protein GSDMD to produce
the GSDMD-N terminal fragment, which inserts into the podocyte
membrane to form pores, leading to cytoplasmic content leakage and
triggering podocyte pyroptosis, thereby exacerbating DN progression
(Fig. 8) (173).
DN is driven by a complex, interconnected network of
inflammatory and fibrotic signaling cascades, in which the NLRP3
inflammasome acts as a key synergistic hub rather than an exclusive
dominant pathogenic mechanism. The canonical TGF-/Smad pathway, as
the core fibrotic driver that mediates excessive ECM deposition and
tubular EMT in DN, engages in bidirectional crosstalk with the
NLRP3 inflammasome: TGF-upregulates TXNIP expression to potentiate
NLRP3 activation, while IL-1 generated by NLRP3 inflammasome
signaling in turn amplifies TGF-mediated renal fibrosis, forming a
pro-fibrotic positive feedback loop (174,175). The TLR4/MAPK/NF-κB pathway
serves as a pivotal upstream priming signal for the global
inflammatory cascade in DN and operates in parallel with the NLRP3
axis, transcriptionally inducing the expression of NLRP3, pro-IL-1β
and pro-IL-18 and cooperating with the NLRP3 inflammasome to
promote renal macrophage infiltration and sustained inflammatory
responses, thereby collectively exacerbating inflammatory renal
injury (7,144). The AGEs/RAGE pathway
constitutes a core metabolic-immune linkage in DN, whereby
hyperglycemia-induced AGEs bind to their receptor RAGE
simultaneously and activate the NLRP3 inflammasome and the
MAPK/NF-κB signaling cascade, acting as a common upstream trigger
that bridges metabolic disorders and inflammatory activation across
multiple DN-related pathways (21,176). The JAK/STAT pathway primarily
mediates the transduction of pro-inflammatory cytokines including
IL-6 and IFN-γ in DN; its activation facilitates the assembly of
the NLRP3 inflammasome, whereas inflammatory cytokines released
upon NLRP3 activation further stimulate the JAK/STAT cascade,
establishing a signal amplification loop that aggravates renal
inflammatory damage (144,177,178). The Wnt/β-catenin pathway
promotes podocyte dedifferentiation and renal fibrosis, with its
activation closely associated with OS, a key initiator of NLRP3
inflammasome activation. The Wnt/β-catenin pathway acts in parallel
with NLRP3-mediated pyroptosis to jointly induce renal structural
lesions and functional deterioration (179-181). Collectively, these pathways
interact and synergize to propel the pathological progression of
DN, and the NLRP3 inflammasome functions as a key contributory
component within this multi-pathway regulatory network.
Targeting the NLRP3 inflammasome represents a
promising contributory therapeutic strategy for DN, complementing
interventions against other major inflammatory and fibrotic
pathways. Notable progress has been made in developing
NLRP3-specific inhibitors. MCC950, the first selective NLRP3
inhibitor to enter preclinical studies, has demonstrated marked
efficacy in db/db mouse models of DN. By suppressing the
NLRP3/caspase-1/IL-1β pathway, MCC950 reduced renal inflammation
and fibrosis, improved renal function parameters and alleviated
glomerular basement membrane thickening as well as podocyte injury
(182,183). BAY11-7082, a compound initially
identified as an NF-κB inhibitor, has been rigorously verified to
suppress NLRP3 inflammasome activation specifically by inhibiting
NLRP3 ATPase activity in DN models, and this renoprotective effect
is independent of its canonical NF-κB inhibitory function. The
specificity of this mechanism in DN is supported by multiple lines
of evidence: i) BAY11-7082 directly binds to the NACHT (ATPase)
domain of NLRP3 in renal intrinsic cells and diabetic mouse
kidneys, without targeting the ATPase of other NLR family
inflammasomes (such as NLRC4 and AIM2) (184); ii) the anti-inflammatory and
renal protective effects of BAY11-7082 are completely lost in
NLRP3-knockout diabetic mice and NLRP3-silenced renal cells,
excluding off-target anti-inflammatory interference (183); and iii) the low concentration
used in DN studies exerts no notable cytotoxicity on renal cells
(normal cell viability and apoptosis rate), ruling out non-specific
cytotoxic effects as a confounding factor (185). Other studies have shown that
dapagliflozin inhibits the miR-155-5p/HO-1/NLRP3 axis in diabetic
models, reduces pyroptosis and delays DN development (186). In addition, multiple pathways
exist to reduce DN by inhibiting NLRP3 (187-189) (Table II) (190-201).
With the development of traditional Chinese
medicine, certain monomers of Chinese herbs have been identified
for use in the treatment of DN. Astragaloside IV (AS-IV), the main
active ingredient of Astragalus membranaceus, has
pharmacological effects including anti-inflammatory, antioxidant,
hypoglycemic, lipid-lowering and anti-fibrotic effects (202). Studies have shown that AS-IV
inhibits hyperglycemia-induced NLRP3 activation in mouse podocytes
and reduces podocyte death by upregulating SIRT6 and downregulating
HIF-1α, thereby suppressing the expression of NLRP3, caspase-1,
GSDMD, IL-1β and IL-18. In addition, AS-IV increases endogenous
Klotho expression levels by modulating the NF-κB/NLRP3 signaling
pathway while improving OS, protecting glomerular podocytes,
reducing inflammation and alleviating endoplasmic reticulum stress
(203-205). Triptolide, an essential active
ingredient extracted from the traditional Chinese medicine
Tripterygium wilfordii, reduces hyperglycemia-induced EMT in
podocytes, inhibits NLRP3 inflammasome activation and prevents
pyroptosis of podocytes (206).
The mechanism is associated with upregulation of Nrf2 and HO-1
protein expression and a reduction in ROS levels (207,208). Ginsenosides are active monomer
components of ginseng and have a wide range of pharmacological
properties, including antioxidant, anti-inflammatory, hypoglycemic
and anti-aging effects (209).
Different ginsenosides exert their effects through distinct
mechanisms. Compound K inhibits TXNIP-mediated NLRP3 inflammasome
activation, thereby reducing the expression of inflammatory
cytokines such as IL-1β and IL-18, improving renal function and
mitigating inflammatory injury (210). Ginsenoside Rg1 protects DN
podocytes from hyperlipidemic-induced damage through the
mTOR/NF-κB/NLRP3 signaling axis (211). Ginsenoside Rg3 inhibits NLRP3
inflammasome activation in human and mouse macrophages, blocks
IL-1β secretion and caspase-1 activation and improves renal injury
(212). Ginsenoside Rg5
inhibits NLRP3 inflammasome activation, reduces inflammatory
response, lowers blood glucose, creatinine and urea nitrogen
levels, and improves renal pathology (213). Other monomers of traditional
Chinese medicine have been reported to delay the progression of DN
by inhibiting NLRP3 (Table SI)
(203-251).
The application of traditional Chinese medicine
prescriptions has also demonstrated notable therapeutic benefits in
DN. Buzhong yiqi decoction is reported to inhibit activation of the
NLRP3 inflammasome pathway, restore the Th1/Th2 immune balance and
alleviate DN progression (237). The Yi shen pai du formula,
composed of Astragalus membranaceus, rhubarb, leeches and
silkworm pupae, can reduce OS and the release of inflammatory
factors, relieve renal fibrosis, prevent EMT in renal tubular
epithelial cells and inhibit the formation of NLRP3 inflammasomes,
mainly by activating the Nrf2 pathway (238,239). Zuogui-jiangtang-yishen is
derived from the classic Chinese medicine formula Zuogui pills and
targets the mROS-NLRP3 axis, inhibiting intestinal-origin
Trimethylamine N-oxide-induced pyroptosis, improving glucose and
lipid metabolism disorders, protecting renal function and delaying
DN progression (240,241). The Yiqi-huoxue-jiangzhuo
formula has been shown to improve chronic kidney disease (CKD) and
its associated complications. Its cardioprotective effects in CKD
mice are associated with modulation of the gut microbiota and
inhibition of the NLRP3 inflammasome (242,251). Tongluo yishen decoction,
composed of Salvia miltiorrhiza and Stephania
tetrandra, can improve renal fibrosis by regulating
NLRP3-mediated cell death and had a notable effect in rat models
after 2 weeks of intervention (243,244). Numerous traditional Chinese
medicine prescriptions have also been reported to reduce DN by
inhibiting NLRP3 (Table SI)
(203-251).
Gene therapy refers to introducing functional
exogenous genes into target cells to correct or compensate for
diseases caused by defective or abnormal genes. It also encompasses
genetic modification techniques in which exogenous genes are
delivered into appropriate recipient cells so that their gene
products exert therapeutic effects. In a broader sense, gene
therapy includes various strategies and emerging technologies that
intervene at the DNA level to treat human diseases. Specifically,
in the context of the present topic, gene therapy can be applied as
a novel strategy for NLRP3 inflammasome-mediated therapeutic
targeting in DN, by regulating the expression of NLRP3
inflammasome-related genes or delivering functional genes to
inhibit NLRP3-mediated neuronal pyroptosis and neuroinflammation,
thereby achieving therapeutic effects on diabetic neuropathy
(252,253).
MicroRNAs (miRNAs/miRs) are key post-transcriptional
regulators involved in metabolic and inflammatory processes,
offering new insights into the molecular mechanisms underlying DN.
Non-coding RNAs modulate gene expression through epigenetic
pathways and thus present opportunities for the development of
preventive therapeutics. Experimental studies have shown that
specific miRNAs, such as miR-192, can alleviate kidney injury
(254,255). Long non-coding RNAs (lncRNA),
such as lncRNA MALAT1, can indirectly regulate the NLRP3 pathway by
adsorbing miRNA. This non-coding RNA-targeted intervention offers a
new direction for gene therapy (256,257) (Table III) (258-263). Silencing the NLRP3 or ASC gene
using RNA interference may effectively reduce inflammasome
expression in renal tissue, thereby attenuating the inflammatory
response.
The CRISPR-Cas9 system has emerged as a powerful
gene-editing tool capable of precisely cutting, inserting or
deleting DNA sequences. Knocking out the NLRP3 gene with CRISPR can
directly block inflammasome assembly and activation, reduce IL-1β
and IL-18 secretion, and thereby alleviate renal inflammation
(264,265). Although the application of the
technology in kidney disease is still in its early stages, its
precision offers a promising direction for targeted therapy
(Table IV) (266-270).
The present review outlines the multifactorial
pathogenesis of DN. It should be emphasized that the NLRP3
inflammasome does not operate as the sole dominant mechanism in DN;
rather, it functions in concert with other pathways. In contrast to
existing reviews, the present study proposes a novel hierarchical
regulatory framework for NLRP3 inflammasome activation in DN,
systematically dissects the mitochondrial metabolic-cGAS-STING
synergy mechanism, and provides evidence-stratified therapeutic
strategies for clinical translation as a complementary approach to
other anti-inflammatory and anti-fibrotic therapies. Several
pathways involved in NLRP3 inflammasome activation were discussed,
including key signaling molecules such as NF-κB, TXNIP, Nrf2 and
PI3K/Akt, which act via interconnecting mechanisms and contribute
to the complexity of inflammasome activation. In addition,
therapeutic strategies targeting NLRP3 inflammasomes to alleviate
renal injury in DN were summarized. Overall, the multifactorial
pathogenesis of DN remains incompletely understood. The NLRP3
inflammasome is a key contributory hub within the inflammatory
network of DN, acting in synergy with TGF-β/Smad, TLR4/NF-κB and
other core pathways. Further investigation into the crosstalk
between NLRP3 and parallel pathways will facilitate the development
of combination therapeutic strategies for DN, with the expectation
that more effective and precise clinical interventions will be
developed in the future.
Not applicable.
HY and XW conceived and supervised the present
study; HY, XW, ShLi, XG, TX, SaLi, RY and TL analyzed data; XW
wrote the manuscript. All authors reviewed the results and approved
the final version of the manuscript. Data authentication not
applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
This research is supported by the Doctoral Research Start-up
Fund Project of Mudanjiang Medical University (grant no.
2021-MYBSKY-027); Heilongjiang Province Natural Science Foundation
Project (grant no. SS2023H003); Heilongjiang Province Traditional
Chinese Medicine Research Project (grant no. ZHY2024-212); Basic
Scientific Research Business Research Project of Heilongjiang
(grant no. 2024-KYYWF-0502); Program for Young Talents of Basic
Research in Universities of Heilongjiang Province (grant no.
YQJH2024254).
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![Schematic diagram illustrating the
molecular mechanism through which hyperglycemia and AGEs regulate
NLRP3 inflammasome activation via mitochondrial pathways. This
figure delineates the molecular cascades whereby hyperglycemia and
AGEs (acting via receptor for AGEs [RAGE] binding) modulate
mitochondrial function, subsequently activating the NLRP3
inflammasome and triggering downstream inflammatory responses and
cell death pathways. Within this schematic, red arrows denote
increased activity or levels, whereas black arrows signify
molecular promotion or activation events. AGEs, advanced glycation
end products; RAGE, receptor for advanced glycation end products;
ROS, reactive oxygen species; CerS6, Ceramide Synthase 6; SDH,
succinate dehydrogenase; OXPHOS, oxidative phosphorylation; mtROS,
mitochondrial reactive oxygen species; mtDNA, mitochondrial DNA;
cGAS, cyclic GMP-AMP synthase; cGAMP, cyclic guanosine
monophosphate-adenosine monophosphate; SITNG, stimulator of
interferon genes; TBK1, TANK-binding kinase 1; NLRP3, NOD-like
receptor family pyrin domain containing 3; IRF3, interferon
regulatory factor 3; GSDM, Gasdermin; H3K18la, Histone H3 Lysine 18
Lactylation; HIF-1α, hypoxia inducible factor 1 subunit α.](/article_images/ijmm/58/1/ijmm-58-01-05847-g05.jpg)
