NLRP3 Inflammasome Activation in Diabetes: A Molecular Nexus between Inflammation and Cardiac Dysfunction
DOI:
https://doi.org/10.12982/BSCM.2026.54คำสำคัญ:
Cardiac fibrosis, caspase-1, diabetic cardiomyopathy (DCM), hyperglycemia, IL-1β, IL-18, NLRP3 inflammasome, oxidative stress, pyroptosis, TXNIPบทคัดย่อ
Diabetes mellitus (DM) is a major global health concern closely associated
with cardiovascular diseases, particularly diabetic cardiomyopathy (DCM), which can develop independently of hypertension or coronary artery disease. Chronic hyperglycemia in DM promotes oxidative stress and
inflammation, driving myocardial dysfunction and fibrosis. The NLRP3
inflammasome, a cytosolic multiprotein complex, is a central mediator linking metabolic stress to innate immunity. In both type 1 and type 2 DM, it senses injurious stimuli including mitochondrial reactive oxygen species (ROS), ATP, and advanced glycation end-products (AGEs) activating caspase-1 and triggering the release of pro-inflammatory cytokines IL-1 and IL-18, thereby promoting inflammation and pyroptotic cell death.
This review focuses on NLRP3 inflammasome activation in the diabetic heart, emphasizing upstream regulators such as thioredoxin-interacting protein (TXNIP) and NF-B and downstream consequences including cardiomyocyte death, fibrosis, and contractile maladaptation. Therapeutic approaches targeting NLRP3 range from conventional drugs, including metformin and SGLT2 inhibitors, to specific inhibitors such as MCC950 and colchicine, highlighting their cardioprotective potential. Emerging evidence on microRNA-mediated regulation, exosomal signalling, and
inter-organ communication further elucidates how systemic inflammation contributes to heart failure in diabetic patients.
Despite progress, significant gaps remain regarding the cell-type specificity, temporal dynamics, and epigenetic control of NLRP3 activation in the diabetic myocardium, limiting translation of preclinical findings into effective therapies. Understanding these mechanisms may enable precise, targeted interventions to mitigate inflammation-driven cardiac injury in DM.
เอกสารอ้างอิง
Ding S, Xu S, Ma Y, Liu G, Jang H, Fang J. Modulatory mechanisms of the NLRP3 inflammasomes in diabetes. Biomolecules. 2019;9:850. PubMed PMID: 31835423
Fujino M, Ishihara M, Honda S, Kawakami S, Yamane T, Nagai T, Nakao K, Kanaya T, Kumasaka L, Asaumi Y, Arakawa T. Impact of acute and chronic hyperglycemia on in-hospital outcomes of patients with acute myocardial infarction. Am J Cardiol. 2014;114:1789-93.
Cheng CY, Hao WR, Liu JC, Cheng TH. Teneligliptin mitigates diabetic cardiomyopathy through inflammasome inhibition: insights from experimental studies. World J Diabetes. 2024;15:2370-5.
Nakamura K, Miyoshi T, Yoshida M, Akagi S, Saito Y, Ejiri K, et al. Pathophysiology and treatment of diabetic cardiomyopathy and heart failure in patients with diabetes mellitus. Int J Mol Sci. 2022;23:3587. PubMed PMID: 35408946
Kenny HC, Abel ED. Heart failure in type 2 diabetes mellitus: impact of glucose-lowering agents, heart failure therapies, and novel therapeutic strategies. Circ Res. 2019;124:121-41.
Khovidhunkit W, Kim MS, Memon RA, Shigenaga JK, Moser AH, Feingold KR, et al. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res. 2004;45:1169-96.
Cummings DE, Schwartz MW. Genetics and pathophysiology of human obesity. Annu Rev Med. 2003; 54:453-71.
Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115:1111-9.
Schroder K, Zhou R, Tschopp J. The NLRP3 inflammasome: a sensor for metabolic danger? Science. 2010;327(5963):296-300.
Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011;17:179-88.
Lee HM, Kim JJ, Kim HJ, Shong M, Ku BJ, Jo EK. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes. 2013;62:194-204.
Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821-32.
Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477-89.
Boucher D, Monteleone M, Coll RC, Chen KW, Ross CM, Teo JL, et al. Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity. J Exp Med. 2018;215:827-40.
Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526(7575):666-71.
Sharif H, Wang L, Wang WL, Magupalli VG, Andreeva L, Qiao Q, et al. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature. 2019;570(7761):338-43.
Andreeva L, David L, Rawson S, Shen C, Pasricha T, Pelegrin P, et al. NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation. Cell. 2021;184:6299-312.
Tapia-Abellán A, Angosto-Bazarra D, Alarcón-Vila C, Baños MC, Hafner-Bratkovič I, Oliva B, et al. Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation. Sci Adv. 2021;7:eabf4468. PubMed PMID: 34524838
Xiao L, Magupalli VG, Wu H. Cryo-EM structures of the active NLRP3 inflammasome disc. Nature. 2023; 613(7944):595-600.
Moasses Ghafary S, Soriano-Teruel PM, Lotfollahzadeh S, Sancho M, Serrano-Candelas E, Karami F, et al. Identification of NLRP3PYD homo-oligomerization inhibitors with anti-inflammatory activity. Int J Mol Sci. 2022;23:1651. PubMed PMID: 35163573
Lu A, Magupalli VG, Ruan J, Yin Q, Atianand MK, Vos MR, et al. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell. 2014;156:1193-206.
Xiao L, Magupalli VG, Wu H. Cryo-EM structures of the active NLRP3 inflammasome disc. Nature. 2023;613(7944):595-600.
Sharma M, de Alba E. Structure, activation and regulation of NLRP3 and AIM2 inflammasomes. Int J Mol Sci. 2021;22:872. PubMed PMID: 33467177
Wang Z, Zhang S, Xiao Y, Zhang W, Wu S, Qin T, et al. NLRP3 inflammasome and inflammatory diseases. Oxid Med Cell Longev. 2020;2020:4063562. PubMed PMID: 32148650
Chen Y, Wang L, Pitzer AL, Li X, Li PL, Zhang Y. Contribution of redox-dependent activation of endothelial Nlrp3 inflammasomes to hyperglycemia-induced endothelial dysfunction. J Mol Med (Berl). 2016;94:1335-47.
Jankauskas SS, Kansakar U, Varzideh F, Wilson S, Mone P, Lombardi A, Gambardella J, Santulli G. Heart failure in diabetes. Metabolism. 2021;125:154910. PubMed PMID: 34627874
Sun Y, Ding S. NLRP3 inflammasome in diabetic cardiomyopathy and exercise intervention. Int J Mol Sci. 2021;22:13228. PubMed PMID: 34948026
Wang G, Ma TY, Huang K, Zhong JH, Lu SJ, Li JJ. Role of pyroptosis in diabetic cardiomyopathy: an updated review. Front Endocrinol (Lausanne). 2024;14:1322907. PubMed PMID: 38250736
Luo B, Huang F, Liu Y, Liang Y, Wei Z, Ke H, et al. NLRP3 inflammasome as a molecular marker in diabetic cardiomyopathy. Front Physiol. 2017;8:519. PubMed PMID: 28790925
Zhao L, Hu H, Zhang L, Liu Z, Huang Y, Liu Q, et al. Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions. MedComm (2020). 2024;5:e516. PubMed PMID: 38617433
Zhang L, Ai C, Bai M, Niu J, Zhang Z. NLRP3 inflammasome/pyroptosis: a key driving force in diabetic cardiomyopathy. Int J Mol Sci. 2022;23:10632. PubMed PMID: 36142531
Li JP, Qiu S, Tai GJ, Liu YM, Wei W, Fu MM, et al. NLRP3 inflammasome-modulated angiogenic function of EPC via PI3K/Akt/mTOR pathway in diabetic myocardial infarction. Cardiovasc Diabetol. 2025;24:6. PubMed PMID: 39762890
Matsumori A. Nuclear factor-B is a prime candidate for the diagnosis and control of inflammatory cardiovascular disease. Eur Cardiol. 2023;18:e40. PubMed PMID: 37456770
Luo B, Li B, Wang W, Liu X, Xia Y, Zhang C, Zhang M, Zhang Y, An F. NLRP3 gene silencing ameliorates diabetic cardiomyopathy in a type 2 diabetes rat model. PLoS One. 2014;9:e104771. PubMed PMID: 25136835
Shah MU, Cliff CL, Squires PE, Lee K, Hills CE. The cardio‐renal‐metabolic role of the nod‐like receptor protein‐3 and senescence‐associated secretory phenotype in early sodium/glucose cotransporter‐2 inhibitor therapy in people with diabetes who have had a myocardial infarction. Diabet Med. 2025;42:e70059. PubMed PMID: 40281683
Wohlford GF, Van Tassell BW, Billingsley HE, Kadariya D, Carbone S, Mihalick VL, et al. Phase 1b, randomized, double-blinded, dose escalation, single-center, repeat dose safety and pharmacodynamics study of the oral nlrp3 inhibitor dapansutrile in subjects with NYHA ii-iii systolic heart failure. J Cardiovasc Pharmacol. 2021;77:49-60.
Luo B, Li B, Wang W, Liu X, Liu X, Xia Y, et al. Rosuvastatin alleviates diabetic cardiomyopathy by inhibiting NLRP3 inflammasome and MAPK pathways in a type 2 diabetes rat model. Cardiovasc Drugs Ther. 2014;28:33-43.
Frangogiannis NG. Interleukin-1 in cardiac injury, repair, and remodeling: pathophysiologic and translational concepts. Discoveries (Craiova). 2015;3:e41. PubMed PMID: 26273700
Mauro AG, Bonaventura A, Mezzaroma E, Quader M, Toldo S. NLRP3 inflammasome in acute myocardial infarction. J Cardiovasc Pharmacol. 2019;74:175-87.
Toldo S, Abbate A. The role of the NLRP3 inflammasome and pyroptosis in cardiovascular diseases. Nat Rev Cardiol. 2024;21:219-37.
Phungphong S, Suthivanich P, Boonhoh W, Punsawad C, Cheng Z, Bupha-Intr T. Targeting NLRP3 inflammasome attenuates cardiac pyroptosis and fibrosis in estrogen-deficient diabetic rats. Pflugers Arch. 2025; 477:935-52.
Li Y, Zhang Y, Lu J, Yin Y, Xie J, Xu B. Anti-inflammatory mechanisms and research progress of colchicine in atherosclerotic therapy. J Cell Mol Med. 2021;25: 8087-94.
Sharma A, Choi JS, Stefanovic N, Al-Sharea A, Simpson DS, Mukhamedova N, et al. Specific NLRP3 inhibition protects against diabetes-associated atherosclerosis. Diabetes. 2021;70:772-87.
Lu X, Tan Q, Ma J, Zhang J, Yu P. Emerging role of LncRNA regulation for NLRP3 inflammasome in diabetes complications. Front Cell Dev Biol. 2022;9:792401. PubMed PMID: 35087834
Senesi P, Ferrulli A, Luzi L, Terruzzi I. Diabetes mellitus and cardiovascular diseases: nutraceutical interventions related to caloric restriction. Int J Mol Sci. 2021;22:7772. PubMed PMID: 34360538
Sharma A, Tate M, Mathew G, Vince JE, Ritchie RH, De Haan JB. Oxidative stress and NLRP3-inflammasome activity as significant drivers of diabetic cardiovascular complications: therapeutic implications. Front Physiol. 2018;9:114. PubMed PMID: 29515457
Toldo S, Abbate A. The NLRP3 inflammasome in acute myocardial infarction. Nat Rev Cardiol. 2018;15:203-14.
Van Hout GP, Bosch L, Ellenbroek GH, De Haan JJ, Van Solinge WW, Cooper MA, et al. The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction. Eur Heart J. 2017;38:828-36.
Wang Y, Gao W, Shi X, Ding J, Liu W, He H, Wang K, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017;547 (7661):99-103.
de Rivero Vaccari JC, Dietrich WD, Keane RW, de Rivero Vaccari JP. The inflammasome in times of COVID-19. Front Immunol. 2020;11:583373. PubMed PMID: 33149733
Parker LE, Papanicolaou KN, Zalesak-Kravec S, Weinberger EM, Kane MA, Foster DB. Retinoic acid signaling and metabolism in heart failure. Am J Physiol Heart Circ Physiol. 2025;328:H792-H813. PubMed PMID: 39933792
