Open research questions in Inflammasome and immune disorders

What the literature leaves open

• Inflammasomes have emerged as critical regulators of inflammation and programmed cell death within the female reproductive system. Accumulating evidence demonstrates that dysregulation of apoptosis, pyroptosis, and necroptosis contributes to the development and progression of several reproductive disorders, including endometriosis, PCOS, PE, RPL, POI, and implantation- related complications. Among inflammasome complexes, NLRP3 has received the greatest attention because of its ability to promote IL-1β and IL-18 maturation and to drive inflammatory responses that disrupt reproductive tissue homeostasis. Recent advances have revealed extensive crosstalk among different regulated cell death pathways, leading to the concept of PANoptosis as an integrated inflammatory cell death program. Although several reproductive disorders exhibit concurrent activation of apoptosis-, pyroptosis-, and necroptosis-associated signaling pathways, direct evidence demonstrating canonical PANoptosome formation and PANoptosis activation in reproductive tissues remains limited. Therefore, PANoptosis should currently be regarded as a promising and emerging mechanistic framework rather than a fully established pathogenic pathway in reproductive diseases. Therapeutic modulation of inflammasome-associated cell death pathways represents a promising avenue for future intervention. Experimental and preclinical studies have shown encouraging results with NLRP3 inhibitors, IL-1β-targeted therapies, and agents capable of modulating pyroptotic and inflammatory signaling. However, because inflammasome activation also participates in normal physiological processes such as ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT implantation, decidualization, and placental development, future therapeutic strategies should focus on restoring immune and inflammatory balance rather than completely suppressing these pathways. Overall, a better understanding of the molecular interactions among inflammasomes, regulated cell death pathways, and reproductive physiology may facilitate the development of novel biomarkers and targeted therapies for reproductive disorders. Future studies integrating molecular, cellular, and clinical approaches are needed to define the precise contribution of PANoptosis-related mechanisms and to translate these findings into improved reproductive health outcomes.

  Inflammasome-mediated cell death pathways in female reproductive disorders: from apoptosis, pyroptosis, and necroptosis to PANoptosis · 2026 · DOI

• Poly-gallic acid (PGAL), enzymatically synthesized polymer, has demonstrated antioxidant and anti-inflammatory properties; however, its effect on MSU-induced inflammasome activation remains unclear.

  Electrostatic Interaction of Enzyme-Mediated Poly(gallic acid) with Monosodium Urate Crystals Attenuates Inflammasome Activation and Oxidative Stress · 2026 · DOI

• While terminal complement inhibitors improve survival, the precise intracellular mechanisms driving the destruction of PNH erythrocytes remain controversial.

  Complement drives PNH red cell hemolysis independently of inflammasome activation · 2026 · DOI

• The upstream triggers of local inflammasome activation in the sclera and the cell-type specificity of pyroptosis-related events remain to be elucidated.

  Pyroptosis-associated inflammasome activation contributes to scleral remodeling in experimental myopia · 2026 · DOI

• Elucidating the causal mechanisms underlying immunometabolic interactions requires rigorous investigation to determine whether abnormalities in fumarate metabolism directly drive chronic inflam- mation. Key questions remain: does targeted reduction of FH in specific immune cell populations suffice to induce autoimmune pathology? Conversely, can restoration of FH activity, thereby pre- venting fumarate accumulation, ameliorate disease manifestations? Genetic models will be instrumental in addressing these questions. For instance, mice with cell type–specific FH deletion could clarify how cell-autonomous fumarate dysregulation contributes to systemic au- toimmunity. Findings from such models will reflect chronic, high- level fumarate accumulation, which may differ from the effects of acute metabolic rewiring or pharmacological DMF treatment. In human studies, isotope tracing using labeled fumarate or its precursors may help determine whether immune cells actively accumulate fumarate during disease states and whether this metabolic shift precedes clinical exacerbations. Establishing causal inference is essential for validating therapeutic targeting of fumarate-related pathways. Fumarate operates within a complex metabolic network that includes succinate, malate, itaconate, and other immunomodula- tory metabolites. Future investigations should elucidate how fuma- rate-mediated signaling intersects with these related pathways. For example, both succinate and fumarate accumulate in inflammatory macrophages, yet it remains unclear whether their effects on inflammatory pathways are redundant, additive, or antagonistic. Itaconate, which exhibits anti-inflammatory properties and shares protein-succinating activity with fumarate, raises additional ques- tions: could simultaneous elevation of both metabolites produce synergistic anti-inflammatory effects, or might they compete for molecular targets such as KEAP1? Moreover, fumarate’s link to amino acid metabolism via the aspartate-argininosuccinate shunt implies cross-talk with nitrogen handling and arginine metabolism, warranting exploration of how this interplay influences immune polarization. This is particularly relevant as arginine metabolism supports both nitric oxide and polyamine synthesis in macro- phages. Another promising avenue involves examining the interac- including tion between fumarate and energy-sensing systems, AMPK and mTOR. Fumarate accumulation during TCA cycle impairment may trigger energy stress responses, potentially acti- vating AMPK or NRF2. Systems biology approaches, such as integrated metabolomic and transcriptomic analyses, will be essen- tial for mapping system-wide changes following experimental manipulation of fumarate levels in immune cells. Ultimately, a holistic understanding of immunometabolic networks will identify critical regulatory nodes for therapeutic intervention, potentially informing combination strategies—for instance, concurrently en- hancing fumarate signaling while inhibiting succinate activity—to achieve finely tuned immunomodulation.

  Fumarate and fumarate hydratase: an immunometabolite regulator of inflammation and diseases · 2026 · DOI

• The specific mechanisms by which LGALS9 regulates pyroptosis also remain unclear, including how extracellular LGALS9 protein transmits regulatory signals into cells to further affect the onset of acinar cell pyroptosis.

  Platelet-Derived LGALS9 Suppresses NLRP3 Inflammasome-Dependent Pyroptosis in Pancreatic Acinar Cells During Severe Acute Pancreatitis · 2026 · DOI

• Another limitation of this study is the absence of an a priori sample size calculation or power analysis. An additional limitation of this study is that serum literature have analyzed the in Meandros Medical and Dental Journal doi: 10. Further large-scale prospective studies are warranted to clarify their potential the underlying reflect June 2026 27(2):328-338 integration algorithms.

  Assessment of NLRP3, Caspase-1, and IL-18 Levels in Pediatric Sepsis · 2026 · DOI

• The NLRP3 inflammasome has emerged as a critical mediator of cardiovascular pathology; however, translating direct inhibitors from preclinical promise to clinical application has been more challenging than initially anticipated. Despite the exceptional in vitro selectivity of MCC950, its failure due to hepatotoxicity underscores a fundamental limitation of current preclinical models. It highlights the need for early off-target profiling using chemical proteomics before initiating costly trials. This experience enables the evaluation of natural product inhibitors, in which our three-tier evidence classification reveals a significant gap between compounds that have been confirmed to bind biochemically and those that exert their effects through indirect mechanisms. The stringent criteria for direct inhibition are met by only a few natural products, such as oridonin, which covalently modifies Cys279, whereas widely studied flavonoids and polyphenols potentially act through antioxidant or multi-kinase pathways that complicate mechanistic attribution and limit their use as leads for structure-based optimization. therapeutic window, but Cardiovascular applications of NLRP3 inhibitors require indication-specific development strategies. AMI provides a intravenous defined formulations that are not prioritized by most programs. Heart failure addresses a significant unmet need, but it requires long- term safety data that will take years to accumulate. Atherosclerosis it demands FIGURE 3 The translational pipeline for natural product-derived NLRP3 inhibitors in cardiovascular medicine. The progression of candidates from medicinal plants to clinical applications involves a stringent selection process across multiple stages. Discovery and Mechanism Validation (Stages 1–3) prioritize the identification of direct biochemical engagement to distinguish true inhibitors from functional modulators acting through indirect mechanisms like ROS scavenging. Integration of machine learning and chemical proteomics serves to accelerate this validation. Pharmaceutical Optimization (Stage 4) addresses the inherent pharmacokinetic barriers of natural scaffolds, such as the low bioavailability and rapid metabolism observed with oridonin. Advanced nanoparticle formulations and prodrug strategies are utilized to enhance drug-like properties. Cardiovascular Translation (Stages 5–6) advances candidates from preclinical models of atherosclerosis and myocardial injury toward human clinical trials. The clinical failure of MCC950 highlights the necessity of evaluating species-specific off-target risks during translation. Future success depends on the implementation of validated NLRP3-specific biomarkers and stratified trial designs (Original figure created with BioRender.com).

  Direct NLRP3 inflammasome inhibitors for cardiovascular therapeutics: a comparative review of synthetic and natural candidates · 2026 · DOI

• Future development must shift from extensive multi-target intelligent delivery systems capable of screening to sensing the spatiotemporal microenvironment. non-targeted approaches. al., of et 5.3 From mechanism enumeration to paradigm construction: the new precision therapy strategy for sepsis led by sophoridine 1. Precise control of intervention timing. Sepsis is a dynamically evolving process (Delano and Ward, 2016), from the cytokine storm to immunosuppression, where timing is crucial.

  Drug repurposing of sophoridine for sepsis-induced organ injury: from in-depth analysis of a single agent to a multi-target therapeutic paradigm · 2026 · DOI

• Sophoridine’s role in sepsis treatment signifies a paradigm shift to “multi-target, network from “single-target, single-effect” regulation” systemic intervention. Network pharmacology analysis reveals that sophoridine’s action targets overlap with multiple sepsis-related disease targets. Functional analysis (GO) shows it simultaneously covers core pathways like NF-κB, NLRP3, MAPK, and PI3K/Akt, enabling concurrent intervention in the cytokine storm, cellular stress, and immune imbalance. It also participates in inflammation regulation and profoundly influences fundamental life processes like oxidative stress balance, mitochondrial metabolism, and cytoskeletal remodeling.

  Drug repurposing of sophoridine for sepsis-induced organ injury: from in-depth analysis of a single agent to a multi-target therapeutic paradigm · 2026 · DOI

• Inflammasome-mediated pyroptosis is an innate immune mechanism increasingly implicated in inflammatory bowel disease (IBD); however, the upstream molecular signals associated with NLRP3–Caspase-1–GSDMD activation in CD remain insufficiently defined.

  ANGPT1–GABARAP axis modulates NLRP3 inflammasome–mediated pyroptosis in Crohn’s disease · 2026 · DOI

• Here, we characterize an underexplored regulatory mechanism of the pro-inflammatory IL-18 pathway, centered on a truncated IL18R1 isoform with striking species-specific expression differences.

  An ancient retrotransposon provides species-specific tuning of IL-18 inflammatory signaling · 2026 · DOI

• CONCLUSION This study suggests that AIM2 rs2814770 and its combined effect with IFI16 rs1057028 may be increase susceptibility to hepatic fibrosis in CHC patients, highlighting immunogenetic modulation, warranting further research for predictive biomarkers.

  Genetic polymorphism of <i>IFI16</i> and <i>AIM2</i> among Pakistani hepatitis C virus-induced fibrosis patients · 2026 · DOI

• Keywords: Heart failure Cognitive impairment Cardio-neuroinflammatory axis SLC22A3 Histamine NLRP3 inflammasome Heart failure (HF) affects over 64 million individuals worldwide and is strongly associated with cognitive impairment (CI), yet the underlying mechanisms remain poorly understood.

  SLC22A3 deficiency leads to cognitive impairment through the cardio-neuroinflammatory axis mediated HA/H1R/NLRP3 pathway in heart failure mice · 2026 · DOI

• NLRP3 forms an inactive decameric cage, that upon interaction with the trans-Golgi network (TGN) and microtubule organization center (MTOC), leads to inflammasome activation, yet whether non-decamer NLRP3 species form functional inflammasomes remains unclear.

  Non-decameric NLRP3 reveals a TGN/MTOC-distal pathway of inflammasome activation · 2026 · DOI

• Our preliminary findings indicated that SpvC counteracts GSDMD-mediated antibacterial effects to enhance bacterial dissemination, although its functional relevance to epithelial-derived GSDMD and the underlying mechanisms remain unclear.

  Salmonella Effector SpvC Targets SEC23B of Intestinal Epithelial Cells to Resist Gasdermin D-Mediated Protection Against Systemic Infection · 2026 · DOI

• While our study integrates human cohorts, mouse models and in vitro assays to define ACBP/DBI as a systemic biomarker of cell limitations remain. First, organ-specific contribudeath, several tions in humans are inferred from proteomic correlations and therefore require direct tissue-level validation. Second, although pharmacologic inhibitors link specific cell death pathways to ACBP/DBI release, off-target effects cannot be fully excluded. Third, longitudinal dynamics of ACBP/DBI during chronic disease remain unexplored and the causal roles of extracellular ACBP/DBI in inter-organ cross-talk are not directly tested. Finally, population heterogeneity may affect generalizability across ethnicities, ages and comorbidity profiles. DATA AVAILABILITY The data that support the findings of this study are available from the corresponding authors upon reasonable request. REFERENCES 1. Tonon MC, Vaudry H, Chuquet J, Guillebaud F, Fan J, Masmoudi-Kouki O, et al. Endozepines and their receptors: structure, functions and pathophysiological significance. Pharmacol Ther. 2020;208:107386. 2. Duman C, Yaqubi K, Hoffmann A, Acikgoz AA, Korshunov A, Bendszus M, et al. Acyl-CoA-binding protein drives glioblastoma tumorigenesis by sustaining fatty acid oxidation. Cell Metab. 2019;30:274–89 e5. 3. Li S, Mingoia S, Montegut L, Lambertucci F, Chen H, Dong Y, et al. Atlas of expression of acyl CoA binding protein/diazepam binding inhibitor (ACBP/DBI) in human and mouse. Cell Death Dis. 2025;16:134. 4. Li S, Joseph A, Martins I, Kroemer G. Elevated plasma levels of the appetitestimulator ACBP/DBI in fasting and obese subjects. Cell Stress. 2021;5:89–98. 14 Y. Rong et al. 5. Joseph A, Moriceau S, Sica V, Anagnostopoulos G, Pol J, Martins I, et al. Metabolic and psychiatric effects of acyl coenzyme A binding protein (ACBP)/diazepam binding inhibitor (DBI). Cell Death Dis. 2020;11:502. 29. Zhang B, He P, Lawrence JEG, Wang S, Tuck E, Williams BA, et al. A human embryonic limb cell atlas resolved in space and time. Nature. 2024;635:668–78. 30. Team RC R. A language and environment for statistical computing. 2023. https:// 6. Lebrun B, Barbot M, Tonon MC, Prevot V, Leprince J, Troadec JD. Glial endozepines and energy balance: Old peptides with new tricks. Glia. 2021;69:1079–93. 7. Montegut L, Lambertucci F, Moledo-Nodar L, Fiuza-Luces C, Rodriguez-Lopez C, Serra-Rexach JA, et al. Acyl-CoA-binding protein as a driver of pathological aging. Proc Natl Acad Sci USA. 2025;122:e2501584122. 8. Bravo-San Pedro JM, Sica V, Martins I, Pol J, Loos F, Maiuri MC, et al. Acyl-CoAbinding protein is a lipogenic factor that triggers food intake and obesity. Cell Metab. 2019;30:754–67 e9. Isnard S, Royston L, Lin J, Fombuena B, Bu S, Kant S, et al. Distinct plasma concentrations of acyl-CoA-binding protein (ACBP) in HIV progressors and elite controllers. Viruses. 2022;14:453. 9. 10. Montegut L, Abdellatif M, Motino O, Madeo F, Martins I, Quesada V, et al.

  Cell death–induced release of the pro-aging protein acyl CoA binding protein (ACBP) into the circulation · 2026 · DOI

• This study mainly focused on changes in endothelial cell barrier function, while the direct effects of jellyfish venom on specific neural cells such as astrocytes or microglia need to be further clarified, and the interactions among components of the neurovascular unit and their roles in BBB damage also need to be explored in depth.

  Crude Astragalus polysaccharides ameliorate cognitive impairment by preserving blood-brain barrier integrity and suppressing GSDMD-mediated pyroptosis in jellyfish-envenomed mice · 2026 · DOI

• Although basic research on renal fibrosis and cell death is relatively well established, several limitations still exist. One major challenge lies in the profound cellular heterogeneity and the complex interplay among different forms of RCD during renal fibrosis progression. Proximal TECs with varying DNA content, particularly polyploid cells (> 4N), exhibit distinct profibrotic transcriptomic signatures. These cells exhibit dynamic regulation of senescence and apoptosis and are highly heterogeneous in the fibrotic microenvironment. In the context of DKD, singlecell RNA sequencing has revealed a subpopulation of profibrotic TGF-β/Arginase-1 macrophages that promote the differentiation of tethered cells into myofibroblasts through activation of the TGF-β/Smad2/3/YAP signaling axis. Death or dysfunction of these macrophages may exacerbate fibrosis through the release of profibrotic factors. Targeting specific cell death mechanisms or key molecules may offer a novel strategy for treating fibrosis. However, the cellular heterogeneity during fibrosis and the complexity of cell‒cell interactions make precise delivery of drugs to specific cell types extremely challenging. For example, different subpopulations of macrophages may drive or inhibit the fibrotic process. Specific knockdown of tumor protein 53-regulating kinase (TP53RK) in renal tubules or fibroblasts attenuates fibrosis, but delivery systems that distinguish between specific cell types remain elusive [29, 191]. Although existing delivery systems, such as biomimetic high-density lipoprotein nanoparticles, have demonstrated the ability to target injured renal tubules, the complex physiological barriers of the kidney (e.g., the presence of the basement membrane and cellular polarity) may impede the penetration of nanoparticles. Overcoming these challenges in the future will require the combination of single-cell technology to resolve cell subpopulation-specific targets and multiomics approaches to validate the precision and safety of the delivery system. A further limitation is the compensatory crosstalk among distinct RCD pathways. The mechanism of renal fibrosis involves multiple overlapping cell death modalities. When one pathway is inhibited, others may be activated to compensate for its function. Apoptosis signaling may actively inhibit cell death by inhibiting ferroptosis. Excess ROS can induce a variety of forms of RCD, but tumor cells may escape death by modulating ROS-mediated cell death pathways, suggesting that compensatory mechanisms may exist to promote cell survival. These mechanisms play important roles in maintaining cellular homeostasis, escaping therapeutic resistance, and driving disease progression.

  Regulated cell death: a multidimensional regulatory network in the pathogenesis of renal fibrosis · 2026 · DOI

• Despite the robust preclinical data linking the inflamma- some, the gut microbiome, and neurological outcomes, trans- lating these findings into viable human therapeutics faces several substantial hurdles that must direct future research paradigms. The reliance on murine models presents a fun- damental challenge. The baseline immunological profile, specifically the genetic regulation and activation thresholds of the inflammasome, differs significantly between mice and humans. Human macrophages can sometimes bypass the strict dual signal requirement necessary in murine cells, complicating the direct translation of inhibitor efficacy. Standard experimental models often utilize acute, highly toxic compounds (for example, DSS for colitis, MPTP for Parkinson’s disease) to trigger inflammasome activation. These models fail to accurately recapitulate the low-grade, decades-long progression of chronic neuroinflammation and dysbiosis characteristic of human neurodegenerative and metabolic diseases. Unlike SPF mice housed in con- trolled environments, the human microbiome is vastly heterogeneous. Variables such as geography, long-term dietary habits, stress, and circadian disruptions drastically alter microbial composition. A major limitation in clinical cohort studies is the failure to account for routine polyphar- macy. Common medications, notably metformin, proton pump inhibitors, and frequent antibiotic use, profoundly shift the microbiome and alter systemic immune baselines, masking or mimicking specific microbiota-inflammasome interactions. Moreover, there are inconsistencies in method- ologies. The frequent use of 16S rRNA sequencing provides only taxonomic data, whereas functional mapping requires shotgun metagenomics and metabolomics. Standardizing multi-omics approaches is a critical necessity for future studies. Currently, diagnosing central inflammasome activation in living patients is exceedingly difficult. While peripheral markers, such as serum IL-1β, IL-18, or circulating cas- pase-1 indicate systemic inflammation, they do not reliably reflect microglial inflammasome status due to the restric- tive nature of the BBB. There is an urgent clinical need for the development and validation of advanced neuroimaging tools, specifically Positron Emission Tomography (PET) radiotracers that can selectively bind to activated inflam- masome complexes or specific reactive microglial states in vivo. To bridge the translational gap, we believe, the field must embrace models utilizing germ-free mice colonized with the microbiota of specific human cohorts with clini- cally important phenotype to study patient-specific disease trajectories. Moreover, the integration of multi-omics will pave the way for personalized medicine, where a patient’s microbial metabolome and systemic inflammatory mark- ers are profiled to determine if they are ideal candidates for specific inflammasome inhibitors, postbiotics, or precision microbial consortia.

  Importance of the inflammasome in gut-brain axis: from pathological driver to therapeutic target · 2026 · DOI

• Studies have dem- onstrated that inhibiting GSDMD can alleviate UC progression (6, 29); however, the precise mechanisms by which pyroptosis contrib- utes to UC pathogenesis remain unclear. However, studies investigating ZBP1 in UC have been restricted exclusively to intestinal epithelial cells, and the expression and functional signif- icance of ZBP1 in colorectal macrophages remain to be elucidated.

  Emapunil attenuates ulcerative colitis by suppressing Z-DNA binding protein 1 driven pyroptosis and pro-inflammatory polarization in macrophages · 2026 · DOI

• (cid:129) Multi-omics profiling of intestinal and immune compartments to identify molecular pathways linking NLRC4 activation to tissue injury. (cid:129) Longitudinal cytokine and metabolomic analyses in patients to distinguish primary pathogenic drivers from secondary inflammatory responses. (cid:129) Development of refined conditional mouse models targeting epithelial and myeloid compartments to define cell type–specific contributions to disease. threatening NLRC4-MAS, inflammation and sustained disease control40,41,45. leading to rapid stabilization of systemic IL-1 blockade has also been widely employed, often as first-line ther- apy; however, therapeutic responses are frequently incomplete in IL- 18–dominant disease, underscoring cytokine-specific differences in patho- genic contribution and therapeutic sensitivity45. In addition, inhibition of mTOR signaling with rapamycin has shown benefit as an adjunctive strategy by reducing caspase-1 activation and downstream inflammasome- mediated cytokine secretion in patient-derived immune cells46. Tumor necrosis factor (TNF) blockade has been used empirically in a subset of patients, particularly those with severe intestinal inflammation, although clinical responses have been variable and the mechanistic justification remains indirect45,47,48. Interferon-γ (IFN-γ) blockade49 and fecal microbiota transplantation50 have also shown therapeutic benefit in select AIFEC cases, further highlighting the complex and multifactorial nature of disease pathogenesis. Despite the promise of these clinical interventions, interpretation of therapeutic efficacy is constrained by significant limitations. NLRC4- associated autoinflammatory diseases are extremely rare, and most pub- lished clinical experiences are derived from isolated case reports or very small case series. In addition, many reported patients had received multiple immunomodulatory treatments and were frequently treated with multiple agents concurrently, making it difficult to attribute clinical outcomes to a single intervention. Leveraging our newly developed NLRC4 V341A knock- in mouse model, we validated the therapeutic efficacy of both IL-18 and TNF-α blockade in AIFEC40. Notably, this model also revealed that affected pups develop severe systemic inflammation accompanied by profound hypoglycemia. Glucose supplementation significantly attenuated disease severity and improved survival, suggesting that metabolic stress may con- tribute to disease progression in NLRC4-driven autoinflammation. Immunometabolism plays a critical role in regulating immune cell function and tissue homeostasis, and glucose serves as a key energy source during immune activation under conditions of hyperinflammation. Both hyper- glycemia and hypoglycemia have been shown to influence inflammatory responses51–53. Although the precise mechanisms underlying the beneficial effects of glucose supplementation in the AIFEC model remain unclear, several potential pathways have been proposed, including: (1) restoration of immune metabolic balance, (2) reinforcement of epithelial barrier integrity, and (3) promotion of a beneficial microbial environment40. These findings suggest that metabolic dysregulation may contribute to NLRC4-driven pathology. Future studies will be needed to further investigate how hypo- glycemia contributes to autoinflammation and how NLRC4 hyperactivation leads to systemic metabolic alterations.

  Current understanding of the NLRC4 Inflammasome in autoinflammation and enterocolitis · 2026 · DOI

• In summary, the PCD mechanism plays a key role in the progression of AD, and metabolites derived from TCM botanical drugs, with their multi-target and holistic regulation advantages, can intervene in these processes to delay AD development.

  Modulation of programmed cell death by botanical drugs in Alzheimer’s disease: a review from a traditional Chinese medicine perspective · 2026 · DOI

• Boyu Li, Ziheng Cui, Yanji Xu and Meihua Xu* Medical College of Yanbian University, Yanji, Jilin, China Alzheimer’s disease (AD) involves dysregulation of programmed cell death (PCD) pathways, such as apoptosis, ferroptosis, autophagy, and pyroptosis. Current therapeutic options are limited, prompting interest in multi-target regulators such as metabolites derived from traditional Chinese medicine (TCM) botanical drugs. This systematic review critically evaluates recent studies on TCM-derived metabolites that modulate PCD in AD models. We identify key limitations: many metabolites are pan-assay interference metabolites relevance; (PAINS) with questionable pharmacological preclinical models inadequately recapitulate sporadic AD; and translational challenges persist in bioavailability and brain targeting. Future research requires orthogonal validation, improved delivery systems, and stagespecific strategies. This review provides a critical foundation for the development of TCM-inspired therapies for AD.

  Modulation of programmed cell death by botanical drugs in Alzheimer’s disease: a review from a traditional Chinese medicine perspective · 2026 · DOI

• in activation astrocytic GSDMD Pyroptosis has emerged as a critical pathophysiological mechanism in epilepsy, functioning as a molecular bridge that couples neuroinflammation with programmed cell death and neuronal hyperexcitability. As synthesized this review, accumulating evidence reveals cell-type-specific execution of pyroptosis: compromises blood–brain barrier integrity; neuronal pyroptosis engages the TRPM7/ROS/JAK2/STAT3 signaling axis and intersects with NLRP3 inflammasome activation and mitophagy; and microglial these pyroptosis interconnected processes established a self-sustaining feedback loop that lowers seizure thresholds and promotes epileptogenesis. The recent conceptualization of PANoptosis—the coordinated, integrating pyroptosis, inflammatory apoptosis, epileptic neurons—further in highlights the multifaceted regulation of cell death in epilepsy.

  Pyroptosis in epilepsy: from pathophysiological mechanisms to therapeutic strategies · 2026 · DOI

Most-cited papers in Inflammasome and immune disorders

• Cell death · Cell · 2024 · 878 citations
• The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death · Molecular Cell · 2024 · 375 citations
• The role of inflammasomes in human diseases and their potential as therapeutic targets · Signal Transduction and Targeted Therapy · 2024 · 202 citations
• Hegemony of inflammation in atherosclerosis and coronary artery disease · European Journal of Pharmacology · 2024 · 194 citations
• NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation · Cell · 2024 · 191 citations
• Caspase-11/4 and gasdermin D-mediated pyroptosis contributes to podocyte injury in mouse diabetic nephropathy · Acta Pharmacologica Sinica · 2020 · 167 citations
• The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis · Science Immunology · 2024 · 164 citations
• A palmitoylation–depalmitoylation relay spatiotemporally controls GSDMD activation in pyroptosis · Nature Cell Biology · 2024 · 130 citations
• NINJ1 induces plasma membrane rupture and release of damage-associated molecular pattern molecules during ferroptosis · The EMBO Journal · 2024 · 124 citations
• Inflammaging as a target for healthy ageing · Age and Ageing · 2023 · 122 citations

Most recent work

• Mitophagy in Macrophages: A Metabolic Checkpoint in Inflammation‐to‐Repair Transition in Atherosclerosis · Journal of the American Heart Association · 2026
• Macrophage Inflammasome Activation Drives Anti-inflammatory Responses via Neutrophil-Derived ASC Speck Transfer and Gasdermin-Dependent Caspase-1 Inhibition · bioRxiv · 2026
• Cell death–induced release of the pro-aging protein acyl CoA binding protein (ACBP) into the circulation · Cell Death and Differentiation · 2026
• Rg1 activates the AMPK/mTOR-autophagy axis and inhibits the NOD-like receptor 3 inflammasome to alleviate pyroptosis in periodontal ligament fibroblasts · Odontology · 2026
• Effect of Taoren Honghua Jian Granule on NLRP3 Inflammasome Expression in Patients with Stable Coronary Artery Disease: A Multi-Center, Double-blind, Randomized Controlled Trial · Chinese Journal of Integrative Medicine · 2026
• Molecular Dynamics and Virtual Screening of Withania somnifera Phytochemicals as Potential Inhibitors of the Human NLRP9 Pyrin Domain · World Journal of Advanced Engineering Technology and Sciences · 2026
• Serum TNF-α, oxidized LDL, and APOCII as novel predictors for familial mediterranean fever in Egyptian children: a cross-sectional study · Journal of Complementary and Integrative Medicine · 2026
• Immune molecular mechanisms of PANoptosis in sepsis-induced acute kidney injury · Inflammation and Regeneration · 2026
• Dauricine ameliorates intestinal inflammation and oxidative stress in DSS-induced colitis through TLR4/NLRP3/GSDMD-mediated pyroptosis and Nrf2 pathway · Naunyn-Schmiedeberg's Archives of Pharmacology · 2026
• Maresin 1 activates autophagy through SIRT1/PPAR‑γ signaling to mitigate high glucose‑induced pyroptosis in human retinal pigment epithelial cells · Experimental and Therapeutic Medicine · 2026

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