---
title: "PANoptosis in Diabetes and Complications: Mechanisms, Evidence Gaps, and Therapeutic Prospects"
id: "frontiers-in-immunology-18-the-role-of-panoptosis-in-diabetes-and-its-complications-mechanisms-and"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-18-the-role-of-panoptosis-in-diabetes-and-its-complications-mechanisms-and"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1902219"
published_at: "2026-08-19T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# PANoptosis in Diabetes and Complications: Mechanisms, Evidence Gaps, and Therapeutic Prospects
## Provenance & Clinical Metadata
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- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1902219)
- **Published At:** 2026-08-19T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source page provided was the journal landing/navigation for Frontiers in Immunology and did not contain the article text or data for "The role of PANoptosis in diabetes and its complications: mechanisms and therapeutic prospects." - Because the full article content was not present in the supplied source, no study methods, experimental results, pathway diagrams, or clinical recommendations could be extracted. - Key concepts referenced in the original title include **PANoptosis** (a regulated cell death modality) and **diabetes** with its complications; however, the source did not report definitions, mechanistic details, or links between PANoptosis and specific diabetic complications. - The source did not report any specific molecular mediators, sensors, transcriptional regulators, or inflammatory cytokines implicated in PANoptosis in diabetes, nor did it report preclinical or clinical therapeutic interventions targeting PANoptosis. - No evidence, effect sizes, study populations, animal models, or references were available in the provided content to support claims about PANoptosis roles or therapeutic prospects in diabetes. - Given the missing article text, clinicians and researchers should consult the full published article or primary literature to obtain actionable mechanistic details, experimental evidence, and therapeutic proposals concerning **PANoptosis** in **diabetes**. - This summary reflects only what was present on the supplied page (site navigation and journal sections); specific scientific content and conclusions from the referenced article were not reported in the source.
## Clinical Analysis & Structured Key Points
Frontiers | The role of PANoptosis in diabetes and its complications: mechanisms and therapeutic prospects REVIEW article Front. Immunol. , 19 August 2026 Sec. Molecular Innate Immunity Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1902219 Published in Frontiers in Immunology Molecular Innate Immunity 7 impact factor 11.3 citescore Editor & Reviewers Edited by F T Fuminori Tokunaga Reviewed by C H Chen Han A A Ahmed A. Al-Karmalawy Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Table 1 Potential agents or strategies targeting PANoptosis in diabetic complications. View in article REVIEW article Front. Immunol. , 19 August 2026 Sec. Molecular Innate Immunity Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1902219 The role of PANoptosis in diabetes and its complications: mechanisms and therapeutic prospects J Y Jinhong Yan 1 Q W Qiuyue Wang 2 † * F C Fenqin Chen 1 † * 1. Department of Geriatrics, The First Hospital of China Medical University, Shenyang, China 2. Department of Endocrinology, The First Hospital of China Medical University, Shenyang, China Article metrics View details Abstract Diabetes mellitus and its complications are chronic inflammatory diseases driven by metabolic stress. PANoptosis is a recently defined inflammatory lytic cell death pathway that integrates key features of pyroptosis, apoptosis, and necroptosis, and is orchestrated by the PANoptosome complex. Emerging evidence indicates that PANoptosis plays a critical role in the pathogenesis of diabetic complications, prominently in diabetic kidney disease, retinopathy, neuropathy, and cardiomyopathy, with emerging indirect evidence from surrogate models suggesting its potential involvement in diabetic foot ulcers. In this review, we summarise the core molecular mechanisms of PANoptosis, with a focus on the crosstalk among the three programmed cell death pathways under diabetic conditions. We discuss how metabolic stressors such as hyperglycaemia, lipotoxicity, and endoplasmic reticulum stress activate distinct PANoptosome assemblies—including those involving Z-DNA-binding protein 1 (ZBP1), absent in melanoma 2 (AIM2), receptor-interacting protein kinase 1 (RIPK1), NOD-like receptor family pyrin domain-containing protein 12 (NLRP12), NOD-like receptor family pyrin domain-containing protein 3 (NLRP3), and NOD-like receptor family CARD domain-containing protein 5 (NLRC5)—thereby linking metabolic dysregulation to inflammatory cell death. Moreover, we highlight recent advances in targeting PANoptosis as a therapeutic strategy, emphasising interventions directed at upstream metabolic triggers, PANoptosome components, and downstream effector molecules. Finally, we identify key knowledge gaps and propose future research directions to facilitate clinical translation. A deeper understanding of PANoptosis in diabetic complications may pave the way for novel therapeutic approaches that simultaneously block multiple cell death pathways to ameliorate disease progression. 1 Introduction The escalating global diabetes epidemic underscores the urgent need to investigate the pathogenesis of its complications. According to the 11th edition of the Diabetes Atlas (2025), recently published by the International Diabetes Federation, diabetes has become one of the most burdensome non-communicable diseases in human history. As of 2024, approximately 589 million adults aged 20–79 worldwide were affected by diabetes, corresponding to a prevalence of 11.1% ( 1 ). More concerning is that, with the accelerating global population ageing, this figure is projected to reach 853 million by 2050, accounting for 12.96% of the adult population ( 1 ). Chronic low-grade inflammation driven by the innate immune system is a core mechanism underlying the onset and progression of diabetes ( 2 ). In the diabetic milieu, immune cells and metabolic tissues not only sense endogenous damage-associated molecular patterns (DAMPs), such as advanced glycation end products, free fatty acids, and high concentrations of glucose ( 3 , 4 ); they also recognise pathogen-associated molecular patterns (PAMPs), such as bacterial lipopolysaccharide (LPS) and viral nucleic acids ( 5 , 6 ). These DAMPs and PAMPs can be recognised by various pattern recognition receptors, such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors, and absent in melanoma 2 (AIM2) ( 5 , 6 ). Upon binding to their respective ligands, pattern recognition receptors activate downstream signalling cascades, promoting the release of inflammatory cytokines and triggering various forms of programmed cell death (PCD), including pyroptosis, apoptosis, and necroptosis ( 5 , 6 ). Historically, pyroptosis, apoptosis, and necroptosis were generally regarded as independent pathological events ( 3 , 7 ). However, growing evidence suggests that under metabolic stress conditions, such as hyperglycaemia, lipotoxicity, and advanced glycation end products, there is extensive crosstalk among these three PCD pathways ( 8 , 9 ). In recent years, this crosstalk has been systematically elucidated and integrated into a new concept—PANoptosis ( 10 ). It is an inflammatory lytic cell death pathway initiated by specific innate immune sensors and precisely regulated by the PANoptosome, a megacomplex ( 11 , 12 ). Currently, research on PANoptosis is primarily focused on host defence, infectious diseases, and cancer ( 12 , 13 ), consistent with its role as a core component of the innate immune system. However, given that diabetes and its complications are essentially chronic inflammatory diseases driven by metabolic dysregulation, in which persistent endoplasmic reticulum stress (ERS), mitochondrial dysfunction, and the activation of inflammatory signals overlap significantly with the triggers of PANoptosis ( 14 , 15 ), an in-depth exploration of the role of PANoptosis in the field of diabetes undoubtedly holds significant scientific value and clinical translational potential. The common pathological basis of diabetic complications is chronic inflammation, oxidative stress (OS), and various forms of cell death triggered by persistent hyperglycaemia and metabolic disturbances ( 14 , 15 ). As recently comprehensively reviewed, a multitude of inflammatory mediators directly drive the progression of these systemic complications, positioning anti-inflammatory strategies as a critical gateway for developing novel effective treatments ( 2 ). PCD is a key mechanism underlying diabetes-related tissue damage, and modulating specific PCD pathways can partially attenuate disease progression ( 16 – 18 ). However, clinical and preclinical studies indicate that targeting a single PCD pathway (e.g., pyroptosis or apoptosis alone) has yielded limited therapeutic benefits in certain models of diabetic complications, which may be attributed to extensive crosstalk among PCD pathways ( 7 , 19 ). Therefore, although research on PANoptosis in metabolic diseases is still in its infancy, in-depth exploration of its mechanisms in diabetes and its complications holds promise for identifying novel therapeutic strategies and drug targets. This review summarises the core molecular mechanisms of PANoptosis and highlights recent advances in the field. It focuses on the mechanisms underlying pyroptosis, apoptosis, and necroptosis under diabetic metabolic stress, the complex crosstalk among these three processes, and the potential of targeting PANoptosis as a novel therapeutic strategy. Furthermore, we delve into the potential role of PANoptosis in various diabetic complications, including diabetic kidney disease (DKD), diabetic retinopathy (DR), diabetic neuropathy (DN), diabetic cardiomyopathy (DCM), and diabetic foot ulcer (DFU). More importantly, based on our analysis of the assembly and regulatory mechanisms of the PANoptosome complex, we identify potential therapeutic targets for intervening in diabetes and its complications, aiming to provide a theoretical basis and direction for the development of novel therapies. 2 Programmed cell death As a genetically regulated form of PCD, PCD not only plays a role in the development and maintenance of homeostasis but also exerts a central role in various metabolic diseases ( 4 , 20 ). Depending on whether cell membrane integrity is disrupted and whether an inflammatory response is triggered, PCD can be classified into two major categories: lytic cell death and non-lytic cell death ( 4 , 7 ). Lytic cell death (such as pyroptosis, necroptosis and PANoptosis) is accompanied by cell membrane rupture and the release of large quantities of DAMPs and pro-inflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18), driving a vigorous inflammatory response; in contrast, non-lytic cell death (such as apoptosis) silently eliminates cells through the formation of apoptotic bodies, thereby avoiding the activation of inflammation ( 4 , 7 ). However, this traditional paradigm has been expanded; apoptosis can transition into a lytic and inflammatory form (secondary pyroptosis) via the cleavage of gasdermins, such as gasdermin E (GSDME), orchestrated by classical apoptotic caspases. 2.1 Apoptosis Apoptosis is characterised by cell shrinkage, chromatin condensation, DNA fragmentation, and the formation of apoptotic bodies; this process typically does not trigger a significant inflammatory response. The caspase family primarily executes apoptosis and can be activated via multiple pathways, including the intrinsic mitochondrial pathway and the extrinsic death receptor pathway ( 21 , 22 ). The intrinsic pathway is triggered by intracellular stressors such as DNA damage and growth factor deprivation. These signals upregulate or activate BH3-only proteins, thereby disrupting the homeostatic balance between anti-apoptotic and pro-apoptotic B-cell lymphoma 2 family proteins ( 23 ). This disruption of homeostasis ultimately leads to mitochondrial outer membrane permeabilisation, prompting the release of pro-apoptotic factors, such as cytochrome c, from the mitochondrial intermembrane space into the cytoplasm ( 24 , 25 ).In the cytoplasm, cytochrome c binds to apoptotic protease-activating factor 1 and, in the presence of dATP/ATP, assembles into an apoptosome, which subsequently activates caspase-9 and initiates the caspase cascade ( 26 ). The extrinsic pathway, in contrast, is triggered by the binding of extracellular death ligands, such as Fas ligand (FasL) and tumour necrosis factor-alpha (TNF-α), to their respective receptors. This binding leads to the recruitment of the adaptor protein Fas-associated death domain protein (FADD) and the caspase-8 precursor to the death domain of the receptor’s intracellular domain, forming a death-inducing signalling complex, which subsequently initiates the self-activation of caspase-8 ( 27 , 28 ). Activated caspase-8 can directly cleave and activate downstream effector caspases, caspase-3 and caspase-7, thereby executing the apoptotic programme. Furthermore, caspase-8 can cleave BH3-interacting domain death agonist (Bid), a BH3-only protein, generating its active form, truncated Bid. Truncated Bid subsequently translocates to the mitochondria, where it amplifies endogenous apoptotic signals by promoting mitochondrial outer membrane permeabilisation, thereby linking the two major apoptotic pathways ( 29 , 30 ) ( Figure 1 ). Figure 1 Crosstalk among apoptosis, pyroptosis, and necroptosis. Apaf-1, apoptotic protease-activating factor 1; ASC, apoptosis-associated speck-like protein containing a CARD; DAMP, damage-associated molecular pattern; DISC, death-inducing signalling complex; FADD, Fas-associated death domain protein; Fas, Fas receptor; FasL, Fas ligand; GSDMD, gasdermin D; GSDME, gasdermin E; IL-1β, interleukin-1β; IL-18, interleukin-18; LPS, lipopolysaccharide; MLKL, mixed-lineage kinase-like protein; MOMP, mitochondrial outer membrane permeabilization; NLRP3, NOD-like receptor family pyrin domain-containing protein 3; PAMP, pathogen-associated molecular pattern; RHIM, RIP homotypic interaction motif; RIPK1, receptor-interacting protein kinase 1; RIPK3, receptor-interacting protein kinase 3; tBid, truncated Bid; TNF-α, tumour necrosis factor-alpha; TNFR1, tumour necrosis factor receptor 1. 2.2 Pyroptosis Pyroptosis is a form of programmed necrotic cell death mediated by proteins of the Gasdermin family and accompanied by a strong inflammatory response; its classical pathway relies on the activation of inflammatory caspases (primarily caspase-1) ( 31 ).In this pathway, inflammasomes, represented by NLRP3, act as intracellular multiprotein complexes. Upon recognition of DAMPs or PAMPs by sensor proteins (such as NLRP3), these signals recruit the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC) and trigger assembly, thereby activating caspase-1 ( 32 , 33 ). Activated caspase-1 cleaves and activates the pro-inflammatory cytokine precursors pro-IL-1β and pro-IL-18, driving a robust inflammatory response; simultaneously, it specifically cleaves gasdermin D (GSDMD), releasing the N-terminal domain of GSDMD ( 31 ). The N-terminal domain of GSDMD subsequently oligomerises and forms pores in the cell membrane, directly leading to osmotic swelling, rupture, and the release of cellular contents—the execution phase of pyroptosis ( 34 , 35 ). As research has progressed, our understanding of pyroptosis has moved beyond the classical caspase-1-dependent paradigm. Further studies have shown that caspases-4, 5, and 11 can be directly activated by intracellular LPS, which subsequently cleave GSDMD; this non-classical inflammasome pathway can also effectively induce pyroptosis ( 36 – 38 ) ( Figure 1 ). 2.3 Necroptosis Necroptosis is a form of caspase-independent PCD. Typical morphological features of this process include marked cell swelling and plasma membrane rupture ( 39 ). The classical pathway of necroptosis is triggered by death receptors (such as tumour necrosis factor receptor 1 and Fas) upon ligand stimulation. Its core molecular events depend on the interaction between receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3) via their RIP homotypic interaction motif (RHIM) domains, forming an amyloid-like signalling complex known as the ‘necrosome’. The necrosome subsequently recruits and phosphorylates its key substrate, mixed-lineage kinase-like protein (MLKL) ( 40 , 41 ). Activated MLKL oligomerises and translocates to the plasma membrane, directly disrupting membrane integrity and ultimately leading to cell death ( 39 ) ( Figure 1 ). 3 Crosstalk between pyroptosis, apoptosis, and necroptosis 3.1 Apoptosis and pyroptosis There is a complex interplay between pyroptosis and apoptosis. Taabazuing et al., through studies using dipeptidyl peptidase 8/9 inhibitors to activate caspase-1, found that in the absence of GSDMD, activated caspase-1 alternatively activates caspase-3 and -7, thereby inducing cells to undergo apoptosis. This finding clearly demonstrated, for the first time, that GSDMD is a key molecular switch that diverts cell fate towards pyroptosis ( 42 ). Subsequently, Tsuchiya et al. further validated this phenomenon in various models, including GSDMD-deficient bone marrow-derived macrophages and L929 cells. Their mechanistic studies revealed that following GSDMD knockout, caspase-1 cleaves Bid to generate truncated Bid, which in turn triggers the release of mitochondrial cytochrome c and the activation of caspase-9, ultimately initiating the intrinsic mitochondrial apoptosis pathway ( 43 ). Collectively, these studies reveal that when the pyroptosis pathway is blocked, cells switch to the apoptosis pathway as a backup mechanism. In addition to the shift from pyroptosis to apoptosis following pyroptosis inhibition, recent research has also revealed that the apoptosis pathway actively regulates pyroptosis. Demarco et al. demonstrated that the apoptosis-initiating caspase-8 can directly cleave GSDMD (at the human D276 site), thereby triggering pyroptosis, suggesting that apoptosis can also initiate pro-inflammatory cell death ( 44 ). However, the interaction between these two pathways is not a simple unidirectional activation, but rather exhibits complex synergistic and inhibitory effects. For example, in an osteomyelitis model, the NLRP3 inflammasome and caspase-8 exhibit functional redundancy, with both promoting the maturation and release of IL-1β, illustrating the synergistic interaction between the apoptotic and pyroptotic pathways under specific pathological conditions ( 45 ). Conversely, in cell models such as HEK 293T, THP-1, and RAW 264.7, it has been found that activated executor caspases (caspase-3/7) can specifically cleave the Asp87 site of human GSDMD, producing an inactive p43 fragment, thereby blocking the occurrence of pyroptosis ( 42 ). This negative regulation reveals that, whilst executing its classical death programme, apoptosis simultaneously possesses a ‘braking’ mechanism that inhibits inflammatory cell lysis. In addition to interactions at the cell membrane, crosstalk between pyroptosis and apoptosis is also precisely regulated at the mitochondrial level. Rogers et al. found that the N-terminal domain of GSDME fragment, generated by caspase-3 cleavage, can directly target the mitochondrial membrane, releasing cytochrome c through pore formation, thereby amplifying caspase-3 activation and forming a positive feedback loop ( 46 ). This study also suggests that the N-terminal domain of GSDMD possesses the potential to target mitochondria, implying that this mechanism may have broader biological significance ( 47 ). Furthermore, the cascade of reactions involving inflammasomes and apoptosis-related molecules constitutes another key link between pyroptosis and apoptosis. For example, Lamkanfi’s team used omics technologies to identify caspase-7 as a direct substrate of caspase-1, thereby revealing that the NLRP3/caspase-1/caspase-7 signalling axis mediates inflammasome-driven apoptosis during Salmonella infection ( 48 ). In parallel, research by Gurung et al. established a direct link between the death receptor signalling pathway and the inflammatory response; they found that FADD and caspase-8 are not only key molecules in the apoptotic pathway but also essential nodes for the activation of the NLRP3 inflammasome ( 49 ). This discovery provides direct molecular evidence of how apoptosis participates in and regulates the inflammatory response ( Figure 1 ). 3.2 Apoptosis and necroptosis Caspase-8 is not only the initiator of extrinsic apoptosis, but also the absolute ‘gatekeeper’ of immune homeostasis and suppressor of necroptosis ( 50 ). Under physiological conditions or following simple apoptosis induction, activated caspase-8, through heterodimerisation, specifically cleaves and inactivates RIPK1 and RIPK3, thereby potently inhibiting the formation of the necrosome and the oligomerisation of MLKL. However, under conditions of diabetes-associated viral infection or extreme metabolic stress (such as severe ERS leading to impaired caspase-8 activity), this inhibitory ‘brake’ is released. Subsequently, RIPK1 and RIPK3 bind to each other via their characteristic RHIM, undergo liquid-liquid phase separation-mediated amyloid fibrillation and aggregation, phosphorylate the downstream effector MLKL, thereby committing the cell irreversibly to pro-inflammatory necroptosis. This explains why, in models such as DCM, the simple inhibition of caspase-mediated apoptosis may actually trigger a more intense inflammatory storm ( 51 ) ( Figure 1 ). 3.3 Pyroptosis and necroptosis Pyroptosis and necroptosis not only share downstream inflammatory effectors but also exhibit an independent cross-activation mechanism. Recent studies have shown that MLKL, the executioner protein of necroptosis, can directly trigger the release of IL-1β within the pyropt
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