PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. As a distinct pathway, the execution of PANoptosis cannot be hindered by targeting other cell death pathways, such as pyroptosis, apoptosis, or necroptosis. Instead, targeting key PANoptosome components can serve as a strategy to prevent this form of cell death. Given the physiological relevance in several diseases, PANoptosis is a pivotal therapeutic target. Notably, previous research has primarily focused on the role of PANoptosis in cancer and infectious and inflammatory diseases. By contrast, its role in cardiovascular diseases has not been comprehensively discussed. Here, we review the available evidence on PANoptosis in cardiovascular diseases, including cardiomyopathy, atherosclerosis, myocardial infarction, myocarditis, and aortic aneurysm and dissection, and explore a variety of agents that target PANoptosis, with the overarching goal of providing a novel complementary approach to combatting cardiovascular diseases.

Many inflammatory disorders, including diabetic kidney disease (DKD), are associated with pyroptosis, a type of inflammation-regulated cell death. The purpose of this work was to ascertain the effects of apabetalone, which targets BRD4, a specific inhibitor of the bromodomain (BRD) and extra-terminal (BET) proteins that target bromodomain 2, on kidney injury in DKD. This study utilized pharmacological and genetic approaches to investigate the effects of apabetalone on pyroptosis in db/db mice and human tubular epithelial cells (HK-2). BRD4 levels were elevated in HK-2 cells exposed to high glucose and in db/db mice. Modulating BRD4 levels led to changes in the generation of inflammatory cytokines and cell pyroptosis linked to NLRP3 inflammasome in HK-2 cells and db/db mice. Likewise, these cellular processes were mitigated by apabetalone through inhibition BRD4. Apabetalone or BRD4 siRNA suppressed PLK1 expression in HK-2 cells under high glucose by P300-dependent H3K27 acetylation on the PLK1 gene promoter, as demonstrated through chromatin immunoprecipitation and immunoprecipitation assays. To summarize, apabetalone relieves renal proptosis and fibrosis in DKD. BRD4 regulates the P300/H3K27ac/PLK1 axis, leading to the activation of the NLRP3 inflammasome and subsequent cell pyroptosis, inflammation, and fibrosis. These results may provide new perspectives on DKD treatment.

Pyroptosis, known as one typical mode of programmed cell death, is generally characterized by the cleaved gasdermin family (GSDMs) forming pores in the cell membrane and inducing cell rupture, and the activation of aspartate-specific proteases (caspases) has also been found during this process. Diabetic Kidney Disease (DKD) is caused by the complication of diabetes in the kidney, and the most important kidney\'s function, Glomerular Filtration Rate (GFR), happens to drop to less than 90% of its usual and even lead to kidney failure in severe cases. The persistent inflammatory state induced by high blood glucose implies the key pathology of DKD, and growing evidence shows that pyroptosis serves as a significant contributor to this chronic immune-mediated inflammatory disorder. Currently, the expanded discovery of GSDMs, pyroptosis, and its association with innate immunity has been more attractive, and overwhelming research is needed to sort out the implication of pyroptosis in DKD pathology. In this review, we comb both classical studies and newly founds on pyroptosis, prick off the novel awakening of pyroptosis in DKD, and center on the significance of pyroptosis in DKD treatment, aiming to provide new research targets and treatment strategies on DKD.

Brain injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is the leading cause of neurological dysfunction and death. This study aimed to explore the mechanism of histone deacetylase 6 (HDAC6) in neurofunctional recovery following CA/CPR in rats. A rat model was established by CA/CPR treatment. Adenovirus-packaged sh-HDAC6 was injected into the tail vein. To evaluate the neurofunction of rats, survival time, neurofunctional scores, serum NSE/S100B, and brain water content were measured and Morris water maze test was performed. HDAC6, microRNA (miR)-138-5p, Nod-like receptor protein 3 (NLRP3), and pyroptotic factors levels were determined by real-time quantitative polymerase chain reaction or Western blot assay. HDAC6 and H3K9ac enrichment on miR-138-5p promoter were examined by chromatin immunoprecipitation. miR-138-5p-NLRP3 binding was analyzed by dual-luciferase reporter assay. NLRP3 inflammasome was activated with nigericin sodium salt. After CPR treatment, HDAC6 was highly expressed, while miR-138-5p was downregulated. HDAC6 downregulation improved neurofunction and reduced pyroptosis. HDAC6 enrichment on the miR-138-5p promoter deacetylated H3K9ac, inhibiting miR-138-5p, and promoting NLRP3-mediated pyroptosis. Downregulating miR-138-5p partially reversed the protective effect of HDAC6 inhibition after CPR. In Conclusion, HDAC6 enrichment on miR-138-5p promoter deacetylated H3K9ac, inhibiting miR-138-5p expression and promoting NLRP3-mediated pyroptosis, worsening neurological dysfunction in rats after CPR.

BACKGROUND: Facet joint osteoarthritis (FJOA) is a common lumbar osteoarthritis characterized by degeneration of small joint cartilage. Bushen Huoxue decotion (BSHXD) has good therapeutic effects on OA. Our work aimed to further probe the pharmacological effects of BSHXD-containing serum (BSHXD-CS) on FJOA and define underlying the mechanisms invovled.
METHODS: To establish a FJOA cell model, primary rat chondrocytes were treated with LPS. The mRNA and protein expressions were assessed using qRT-PCR and western blot, respectively. The secretion levels of pro-inflammatory cytokines were measured by ELISA. Cell viability was determined by CCK8 assay. The global m6A level was detected by the kit, and NLRP3 mRNA m6A level was determined by Me-RIP assay. The molecular interactions were analyzed by RIP and RNA pull-down assays.
RESULTS: BSHXD-CS treatment relieved LPS-induced cell injury, inflammation, NLRP3 inflammasome and pyroptosis in chondrocytes (all p < 0.05). LPS-induced NLRP3 upregulation in chondrocytes was related to its high m6A modification level (p < 0.05). It was also observed that BSHXD-CS reduced LPS-induced m6A modification in chondrocytes via repressing STAT3 (all p < 0.05), suggesting BSHXD-CS could repress NLRP3 expression via m6A-dependent manner. Moreover, DAA, a m6A specific inhibitor, was proved to strengthen the protectively roles of BSHXD-CS on LPS-challenged pytoptosis (all p < 0.05).
CONCLUSIONS: BSHXD-CS inhibited NLRP3 inflammasome activation and pyroptosis in chondrocytes to repress OA progression by reducing RNA m6A modification.

BACKGROUND: We previously reported that the HMGB1/TLR4 axis promoted inflammation during the acute phase of intracerebral hemorrhage. Given that this phase is known to involve neuronal pyroptosis and neuroinflammation, here we explore whether HMGB1/TLR signaling activate inflammasome and pyroptosis after intracerebral hemorrhage.
METHODS: Autologous blood was injected into Sprague-Dawley rats to induce intracerebral hemorrhage. Neurological deficits were assessed using a modified neurological severity score. These expression and localization of NLRP1 and NLRP3 inflammasomes, as well as the levels of pyroptosis and pyroptosis-associated proteins were assessed using Western blot or immunocytochemistry. These experiments were repeated in animals that received treatment with short interfering RNAs against NLRP1 or NLRP3, with HMGB1 inhibitor ethyl pyruvate or TLR4 inhibitor TAK-242.
RESULTS: Intracerebral hemorrhage upregulated NLRP1 and NLRP3 in the ipsilateral striatum and increased the proportions of these cells that were pyroptosis-positive. Additionally, the levels of caspase protein family (e.g., pro-caspase-1 and caspase-1), apoptosis-associated speck-like protein (ASC), pro-interleukin-1β (IL-1β), and IL-1β were also elevated. These effects on pyroptosis and associated neurological deficit, were partially reversed by knockdown of NLRP1 or NLRP3, or by inhibition of HMGB1 or TLR4. Inhibition of HMGB1 or TLR4 resulted in the downregulation NLRP3 but not NLRP1.
CONCLUSIONS: The HMGB1/TLR4 signaling may activate the NLRP3 inflammasome during the acute phase of intracerebral hemorrhage, resulting in the inflammatory process known as pyroptosis. These insights suggest potential therapeutic targets for the mitigation tissue injury and associated neurological deficits following hemorrhagic stroke.

Restoring and maintaining the function of endothelial cells is critical for acute respiratory distress syndrome (ARDS). Guanylate binding protein 1(GBP1) is proved to elevated in ARDS patients, but its role and mechanism remains unclear. The objective of this study is to investigate the internal mechanism of GBP1 in lung injury. Our study showed that when the LPS and IFN-γ induced human Pulmonary Microvascular Endothelial Cells (HPMECs) injury model was established, cell viability was significantly reduced, and the levels of GBP1 levels and inflammatory factors were significantly increased. When transfection with si-GBP1, low expression of GBP1 promoted cell proliferation and migration, and decreased the expression of downstream inflammatory factors. Furthermore, the inhibition of GBP1 significantly reduced the occurrence of cell pyroptosis and the expression of NLRP3 and STAT1. Our study indicated that GBP1 alleviates endothelial pyroptosis and inflammation through STAT1 / NLRP3/GSDMD signaling pathway, and GBP1 may be a new target in the treatment of lung injury in the future.

BACKGROUND: Nephrotic syndrome(NS) has emerged as a worldwide public health problem. Renal fibrosis is the most common pathological change from NS to end-stage renal failure, seriously affecting the prognosis of renal disease. Although tremendous efforts have been made to treat NS, specific drug therapies to delay the progression of NS toward end-stage renal failure are limited. Epimedium is generally used to treat kidney disease in traditional Chinese medicine. Icariin is a principal active component of Epimedium.
METHODS: We used Sprague Dawley rats to establish NS models by injecting doxorubicin through the tail vein. Then icariin and prednisone were intragastric administration. Renal function was examined by an automatic biochemical analyzer. Pathology of the kidney was detected by Hematoxylin-Eosin and Masson staining respectively. Furthermore, RT-PCR, Enzyme-Linked Immunosorbent Assay, Immunohistochemistry, Western Blot and Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling staining were employed to detect the proteins related to pyroptosis and EMT. HK-2 cells exposed to doxorubicin were treated with icariin, and cell viability was assessed using the MTT. EMT was assessed using Enzyme-Linked Immunosorbent Assay and Western Blot.
RESULTS: The study showed that icariin significantly improved renal function and renal fibrosis in rats. In addition, icariin effectively decreased NOD-like receptor thermal protein domain associated protein 3,Caspase-1, Gasdermin D, Ly6C, and interleukin (IL)-1β. Notably, treatment with icariin also inhibited the levels of TGF-β, α-SMA and E-cadherin.
CONCLUSIONS: It is confirmed that icariin can improve renal function and alleviate renal fibrosis by inhibiting pyroptosis and the mechanism may be related to epithelial-to-mesenchymal transition. Icariin treatment might be recommended as a new approach for NS.

Clostridium perfringens (C. perfringens), a Gram-positive bacterium, produces a variety of toxins and extracellular enzymes that can lead to disease in both humans and animals. Common symptoms include abdominal swelling, diarrhea, and intestinal inflammation. Severe cases can result in complications like intestinal hemorrhage, edema, and even death. The primary toxins contributing to morbidity in C. perfringens-infected intestines are CPA, CPB, CPB2, CPE, and PFO. Amongst these, CPB, CPB2, and CPE are implicated in apoptosis development, while CPA is associated with cell death, increased intracellular ROS levels, and the release of the inflammatory factor IL-18. However, the exact mechanism by which PFO toxins exert their effects in the infected gut is still unidentified. This study demonstrates that a C. perfringens PFO toxin infection disrupts the intestinal epithelial barrier function through in vitro and in vivo models. This study emphasizes the notable influence of PFO toxins on intestinal barrier integrity in the context of C. perfringens infections. It reveals that PFO toxins increase ROS production by causing mitochondrial damage, triggering pyroptosis in IPEC-J2 cells, and consequently resulting in compromised intestinal barrier function. These results offer a scientific foundation for developing preventive and therapeutic approaches against C. perfringens infections.

BACKGROUND: Thyroid cancer is a rare but increasingly prevalent form of cancer worldwide. The development and progression of thyroid cancer are associated with mitochondrial instability, which refers to alterations in the structure, function, and energy status of mitochondria. These alterations lead to an imbalance in mitochondrial metabolism, causing cellular damage and apoptosis. However, the molecular mechanisms underlying mitochondrial instability and thyroid cancer remain poorly understood.
OBJECTIVE: This study aimed to explore the molecular mechanism of delaying the progression of thyroid cancer by regulating mitochondrial homeostasis through fumarate 1-mediated PGC-1α in vitro.
METHODS: Human papillary thyroid carcinoma cell lines (TPC-1 and K-1) and a normal thyroid cell line (Nthy-ori 3-1) were cultured in this study. TPC-1 cells and K-1 cells were separately transfected with oveRNA-FH1 and oveRNA-NC, designated as the oveRNA-FH1 group, oveRNA- NC group, TPC-1 group, and Nthy-ori 3-1 group. Various assays were performed to assess cell viability, proliferation capacity, invasion and migration abilities, as well as mitochondrial morphology changes and the expression of relevant factors. qRT-PCR and Western blot analysis were carried out to analyze the expression changes of PGC-1α, mitochondrial dynamics-related factors, and pyroptosis genes. The goal of these experiments was to evaluate the impact of FH1 on mitochondrial instability and elucidate the specific mechanisms underlying thyroid cancer and mitochondrial instability.
RESULTS: The results of this study demonstrated that FH1 expression was significantly downregulated in thyroid papillary carcinoma cell lines compared to the normal thyroid cell line. Overexpression of FH1 reduced cell viability and inhibited cell proliferation rate in TPC-1 cells. Furthermore, FH1 overexpression suppressed cell invasion and migration abilities. Abnormal mitochondrial morphological changes were observed in TPC-1 and K-1 cells, whereas FH1 overexpression resulted in relatively normal mitochondria. FH1 overexpression also affected the expression of fusion and fission genes, promoting fission and inhibiting fusion in thyroid cancer cells. Moreover, FH1 overexpression led to increased inflammation and pyroptosis. These conclusions were further verified by in vitro tumor formation experiments.
CONCLUSIONS: FH1 promoted thyroid cancer progression by regulating mitochondrial homeostasis via the PGC-1α-dependent pathway, which affected pyroptosis and apoptosis.