Review Article

Targeting Pyroptosis: New Insights into the Treatment of Diabetic Microvascular Complications

Table 1

Summary of the effects of different methods or drugs on pyroptosis in vivo and in vitro.

Methods/drugsIntervention targetsCell type/animal modelEffects

Ac-YVAD-CMK [29, 33]Caspase-1 inhibitorGECs [29]Reduce the expression of NLRP3, caspase-1, and IL-1β
VX-765 [51]Immortalized mouse podocyte cell line [29, 33]
HBZY-1 [51]
Sodium butyrate [29]Caspase-1-GSDMD,GECsAmeliorate caspase-1-GSDMD-IL-1β/IL-18 canonical pyroptosis pathway and NF-κB/IκB-α signaling pathway
NF-κB/IκB-α
Hirudin [30]IRF2-GSDMDGECs, RTECs, and BMDMsInhibit IRF2-induced GSDMD
MCC950 [32]NLRP3 inhibitordb/db mice and rat mesangial cells<Inhibit the NLRP3/caspase-1/IL-1β pathway
Knockdown TLR4 [37]NALP3/ASC/caspase-1Mouse podocytesInhibit NALP3/ASC/caspase-1 signaling pathway
Knockdown TXNIP [38]TXNIPImmortalized human podocyte cell lineInhibits HG-induced NALP3 inflammasome activation, IL-1β production, and podocyte injury
Overexpress FOXM1 [39]SIRT4MPC5 cellsInhibits NF-κB signaling and NLRP3/caspase-1
sC5b-9NLRP3MPC5 cellsInhibit the expression of NLRP3, caspase-1, GSDMD-N, IL-1β, and IL-18
Knockdown KCNQ1OT1
Upregulate
MiR-486a-3p [40]
miR-21-5p inhibitor [41]miR-21-5p/A20MPC5 cellsInhibit the expression of NLRP3, caspase-1, and IL-1β
Geniposide [42]APMK/SIRT1/NF-κBHFD/STZ-induced DN mice and podocyteActivate APMK/SIRT1 pathway and downregulate the relative levels of p–NF–κB, ASC, cleave-IL-1β, NLRP3, cleave-caspase-1, and GSDMD-N
Catalpol [44]
Atorvastatin [43]MALAT1/miR-200c/NRF2MPC-5 cellsReduce the expression of NLRP3, caspase-1, and GSDMD via the downregulation of MALAT1/miR-200c and promotion of the expression of NRF2
TFA [45]METTL3-dependent m6AMPC-5 cellsDownregulate the expression of GSDMD-N, IL-1β, and IL-18;
PTEN/PI3K/AktUpregulated the protein expression levels of nephrin, ZO-1, WT1, and podocalyxin in podocytes
Naringin [50]NLRP3Rat mesangial cellsReduce the expression of inflammatory factors via the NLRP3-caspase-1-IL-1β/IL-18 signaling pathway
Ginsenoside compound K [51]NLRP3HBZY-1Inhibit ROS-mediated activation of NLRP3 inflammasome and NF-κB/p38 signaling pathway
NF-κB/p38
Downregulate MALAT1 [53]ELAVL1HK-2 cellsInhibit the expression of MALAT1
UpregulateDownregulate the expression of ELAVL1, NLRP3, caspase-1, and IL-1β
MiR-23c [53]
TAK-242 [56]TLR4 inhibitorHK-2 cellsReduce GSDMD-N-induced pyroptosis via the inhibition of TLR4/NF-κB signaling
Downregulate KCNQ1OT1 [57, 65]NLRP3HK-2 cells [57]Inhibits pyroptosis via the NLRP3/caspase-1/IL-1β signaling
UpregulateCorneal endothelial cells [65]
MiR-214 [65]
Knockdown ANRIL [58]TXNIPHK-2 cellsInhibit caspase-1-dependent pyroptosis
Upregulate miR-497 [58]
Resolvin D1 (RvD1) [66]NLRP3STZ-induced diabetic retinopathy ratsInhibit the activation of the NLRP3 inflammasome and downregulate the levels of NLRP3, ASC, cleaved-caspase-1, IL-1β, and IL-18
UpregulateNLRP1 and NOX4HRMECsSuppress pyroptosis by targeting NLRP1 and inhibit the NOX4/ROS/TXNIP/NLRP3 pathway
MiR-590-3p [70]
Overexpress METTL3 [71]miR-25-3p/PTENARPE-19Increase p-Akt level and attenuate the expression of caspase-1, GSDMD, NLRP3, IL-1β and IL-18
KnockdownSTAT3ARPE-19Inhibit STAT3 expression and decrease the expression of pro-caspase-1, caspase-1, NLRP3, IL-1β, and IL-18
CircZNF532 [72]
Upregulate miR-20b-5p [72]
H3 relaxin [73]P2X7R/NLRP3HRMECsAttenuate P2X7R-mediated NLRP3 inflammasome activation and the expression of caspase-1, GSDMD, IL-1β, and IL-18
Silence KCNQ1OT1 [80, 82]TGF-β1/Smads/caspase-1 [80]C57BL/6 mice [80, 82]Alleviate pyroptosis by targeting miR-214-3p
Upregulate miR-214-3p [80, 82]NLRP3/caspase-1 [82]Cardiac fibroblasts of neonatal C57BL/6 mice [80]
AC16 cells and primary cardiomyocytes [82]
Downregulate microRNA-30d [81]<Foxo3a and ARC<Rat cardiomyocytesInhibit pyroptosis via the promotion of the expression of Foxo3a and ARC
Knockdown MALAT1 [83]miR-141-3pH9c2 cellsUpregulate miR-141-3p and attenuate the expression of ASC, caspase-1, GSDMD, GSDMD-N, and NLRP3
Knockdown AIM2 [85]AIM2H9C2 cellsAlleviated GSDMD-N-related pyroptosis
MicroRNA-9 [86]ELAVL1Mouse macropage RAW 264.7 cellsAttenuate the expression of ELAVL1 and inhibit pyroptosis
Upregulate GAS5 [87]miR-34b-3p/AHRHL-1 cellsRepress NLRP3 inflammasome activation-mediated pyroptosis via the inhibition of miR-34b-3p and enhance the gene and protein expression of AHR
SilencemiR-214-3p/caspase-1Mice cardiomyocytesRepress caspase-1-mediated pyroptosis via the inhibition of miR-34b-3p
MIAT [88]
Knockdown circ_0071269 [89]miR-145/GSDMAH9c2 cellsInhibit pyroptosis via the downregulation of GSDMA
STZ-induced DM mice
Overexpress ALDH2 [90]NLRP3H9c2 cellsInhibit NLRP3/caspase-1 dependent pyroptosis
Metformin [91]NLRP3STZ-induced C57BL/6 mice primary cardiomyocytes from neonatal miceInhibit the NLRP3 inflammasome via AMPK/mTOR-dependent effects
Exendin-4 [92]ROS/pAMPK/TXNIPPrimary cardiomyocytesInhibit pyroptosis via the downregulation of TXNIP
HFD-fed mouse model
PQQ [93]NF-κB/NLRP3AC16 cellsDecrease pyroptosis-related protein levels
STZ-induced diabetic mice
Skimmin [94]NLRP3Primary neonatal cardiomyocytesDecrease the expression of NLRP3, caspase-1, and IL-1β
STZ-induced diabetic rat
Empagliflozin [95]NLRP3db/db miceAlleviate the activation of NLRP3 inflammasome and reduce the expression of cleaved-caspase-1, IL-1β, and cleaved-GSDMD

NLRP3: the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3; IL: interleukin; GSDMD: gasdermin D; GSDMA: gasdermin A; GSDMD-N: gasdermin N-terminal; TXNIP: thioredoxin-interacting protein; NF-κB: nuclear factor κB; IκB-α: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; IRF2: interferon regulatory factor 2; MALAT1: metastasis-associated lung adenocarcinoma transcript; NRF2: nuclear factor-erythroid factor 2-related factor 2; LncRNA: long noncoding RNA; TLR4: toll-like receptors-4; ASC: apoptosis-associated speck-like protein containing a CARD; FOXM1: Forkhead box protein M1; SIRT4: sirtuin 4; sC5b-9: the terminal complement complex; RvD1: resolvin D1; TFA: the total flavones of Abelmoschus manihot; MCC950: an inhibitor of NLRP3; APMK: AMP-activated protein kinase; SIRT1: sirtuin 1; AIM2: absent In Melanoma 2; METTL3: methyltransferase-like protein 3; ZO-1: zonula occluden-1; WT1: Wilms tumor protein; p-Akt: phosphorylated Akt; STAT3: signal transducer and activator of transcription 3; P2X7R: the P2X purinoceptor 7; ELAVL1: ELAV-like protein 1; GAS5: growth arrest specific 5; AHR: aryl hydrocarbon receptor; MIAT: myocardial infarction associated transcript; ALDH2: mitochondrial aldehyde dehydrogenase 2; ALDH2: mitochondrial aldehyde dehydrogenase 2; PQQ: pyrroloquinoline quinone; GECs: glomerular endothelial cells; RTECs: renal tubular epithelial cells; BMDMs: bone-marrow-derived macrophages; HRMECs: human retinal microvascular endothelial cells; MPC5 cells: mouse podocyte cell line; HK-2 cells: human tubular cells; ARPE-19: the human retinal pigment epithelium (RPE) cell line; HL-1 cells: cardiac muscle cell line; H9c2 cells: the rat embryonic cardiomyocyte cell line; AC16 cells: human myocardial cells; HFD: high-fat diet; STZ: streptozotocin.