PHYSIOLOGICAL RESEARCH
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2025
·Vol. 74
·期 3
·613
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IF 2
Decui SHAO,Lu BAI,Qian CHEN,Yuhong CHEN,Zhaoxu QIU,Yinuo LIU,Sheng JIN,Yuming WU,Jing DAI
Trimethylamine N-oxide (TMAO) is involved in the development of kidney disease. However, the specific mechanism by which it leads to kidney injury is unclear. This study explored the role of regulated cell death in TMAO-induced kidney injury. We constructed a TMAO-induced chronic kidney injury model by intraperitoneal injection of TMAO (100 μmol/kg/day for three months). Plasma creatinine (Cre) and urea nitrogen (BUN) levels were measured to evaluate kidney function. Masson staining was used to evaluate kidney pathological changes. The expression levels of regulated cell death-related proteins were measured using western blotting. Plasma Cre and BUN, the area of kidney fibrosis in the TMAO group significantly increased. The western blotting results showed cleaved-Caspase-8, Caspase-8, Caspase-1, NOD-like receptor protein 3 (NLRP3), interleukin-1β (IL-1β), cleaved-gasdermin D (cleaved-GSDMD), Z-DNA binding protein 1 (ZBP1), phosphorylation of receptor-interacting protein kinase 3 (RIP3) and mixed-lineage kinase domain-like pseudokinase (MLKL) significantly elevated in the TMAO group. The transferrin receptor 1 (TFR1), ferritin heavy chain (FTH), ferroportin (FPN), nuclear factor erythroid 2-related factor 2 (NRF2), and glutathione peroxidase 4 (GPX4) protein expression in kidney tissue of the TMAO group significantly up-regulated. However, there was no change in iron and MDA levels. The results suggested that PANoptosis, including pyroptosis, apoptosis, and necroptosis components, might be involved in TMAO-induced chronic kidney injury.
研究领域:
肾脏病学
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分子生物学
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细胞生物学
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代谢性疾病
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毒理学
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转化医学
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Cell Reports Medicine
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2025
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IF 10.6
Hui Huang,Zebin Xiao,Wei Feng,Xinran Song,Liang Chen,Lili Huang,Li Ding,Yu Chen
Dendritic cell (DC)-based vaccines for solid tumors face major challenges, including limited tumor-specific antigens and immunosuppressive stroma. Here, we present a therapeutic nanovaccine (UCNP@MOF@MI@FM [UMMF]) composed of a DC/tumor fused cytomembrane-coated UCNP@MOF nanoparticle, co-loaded with a MutT homolog 1 (MTH1) inhibitor and combined with tetrahydrobiopterin (BH4). The fused membrane facilitates dual targeting to tumors and lymph nodes while enabling broad-spectrum tumor antigen presentation. Upon near-infrared (NIR) irradiation, upconversion-triggered reactive oxygen species (ROS) generation and MTH1 inhibition synergistically induce immunogenic PANoptosis, releasing antigens and promoting DCs maturation. Simultaneously, ROS remodels the tumor stroma by depleting collagen and cancer-associated fibroblasts, enhancing T cell infiltration. BH4 counteracts IDO-mediated kynurenine accumulation, reversing immune tolerance and restoring T cell function. This multifunctional platform integrates tumor cell killing, immune priming, and stromal reprogramming, resulting in robust antitumor immunity, reduced relapse, and metastasis suppression. UMMF offers a promising strategy for precision nanoimmunotherapy through controlled PANoptosis and microenvironment modulation.
研究领域:
纳米医学
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免疫治疗
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癌症生物学
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生物工程
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药学
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分子生物学
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EXPERIMENTAL AND MOLECULAR MEDICINE
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2025
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IF 12.9
Wu Jin,Guo Zixiang,Wang Long,Shen Yue,Li Xiang,Zhang Zhewei,Han Xiao,Zhang Jianlan,Cai Kunzhan,Tang Chunbo
Periodontitis is an oral immunoinflammatory disease, and macrophages play a crucial role in its pathophysiology. However, macrophage death during antibacterial activities will exacerbate inflammation and tissue damage. Porphyromonas gingivalis is a major constituent of subgingival biofilm plaques in periodontitis, but the effects and precise molecular mechanisms by which it triggers macrophage death remain unknown. Here we found that P. gingivalis infection notably activated multiple death pathways in bone-marrow-derived macrophages, including pyroptosis, apoptosis and necrosis. Furthermore, using RNA sequencing, we identified that P. gingivalis infection markedly increased the expression of Z-DNA binding protein 1 (Zbp1) in bone-marrow-derived macrophages. Initially identified as an interferon-induced tumor-associated protein, Zbp1 serves as an upstream sensor that regulates cell death by activating PANoptosis. Mechanistically, P. gingivalis induced a mitochondrial stress response, prompting the release of mitochondrial DNA. This mitochondrial DNA then interacted with Zbp1, consequently augmenting its downstream PANoptosis signals. In addition, P. gingivalis stimulated macrophage Zbp1 expression through the Tlr2/4–JNK–Stat3/5 pathway, exacerbating macrophage death. Importantly, blocking the biosynthesis of endogenous Zbp1 by pharmacological delivery with microneedles improved the survival of P. gingivalis -infected macrophages and inhibited periodontal tissue destruction. These findings highlight Zbp1 as a potential therapeutic target for P. gingivalis -induced periodontitis.
研究领域:
免疫学
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口腔医学
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分子生物学
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Materials Today Bio
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2026
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IF 11
Aiyang Tong,Yang Zhou,Yang Ding,Yuelin Zhao,Changna Han,Linlin Wei,Jian Zhao
PANoptosis, a newly characterized form of inflammatory programmed cell death that integrates multiple cell death modalities, offers distinct advantages in both potent tumor cell killing and activation of antitumor immunity. However, strategies that can effectively induce PANoptosis in tumor cells remain scarce. Herein, we constructed a tumor microenvironment-responsive nanoplatform (HA-MnO 2 -FTY720@CaO 2 , HMFC) comprising a CaO 2 core and a MnO 2 shell, loaded with fingolimod (FTY720) and surface-functionalized with hyaluronic acid (HA) for CD44-mediated targeting. Under the mildly acidic and glutathione (GSH)-rich conditions of the tumor microenvironment (TME), the MnO 2 shell degrades, liberating FTY720 and exposing the CaO 2 core. The CaO 2 subsequently decomposes to release Ca 2+ and H 2 O 2. FTY720 inhibits Transient Receptor Potential Melastatin 7 (TRPM7) channels, disrupting Ca 2+ /Mg 2+ homeostasis and thereby provoking severe calcium overload. Simultaneously, MnO 2 depletes GSH and, together with CaO 2 -derived H 2 O 2 , promotes a Fenton-like reaction that generates abundant reactive oxygen species (ROS), thereby disrupting intracellular redox homeostasis. In addition, Mn 2+ released from MnO 2 degradation activates the cGAS–STING pathway, further contributing to DC maturation and antitumor immunity. This orchestrated immune response markedly suppresses tumor growth and when combined with anti-PD-L1 therapy, induces a pronounced abscopal effect. Together, our results indicate that calcium overload, FTY720-mediated TRPM7 inhibition, and MnO 2 -induced redox imbalance can drive PANoptosis, offering a new concept for enhancing cancer immunotherapy.
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BIOORGANIC CHEMISTRY
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2026
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IF 5.1
Beibei Wu,Mingrong Xie,Bangguo Chi,Lili Yang,Changwei Dai,Yongbiao Wei
PANoptosis, a combination of apoptosis, pyroptosis, and necroptosis, plays a key role in the occurrence and development of tumors. In this article, a series of benzimidazole-carbazole-based compounds were developed, which exhibited broad cytotoxicity against eight different cancer cell lines, with significant activity against HepG2 cells. Among them, 3m shows the strongest antiproliferative by preventing HepG2 cells in the G2/M stage. Moreover, 3m can effectively inhibit cell colony formation and migration. Mechanistically, 3m induce PANoptosis in HepG2 cells by upregulating of NLRP3, BAX/BCL2, and cleaved caspase3 expressions, along with the cleavage of gasdermin E (GSDME) into its N-terminal fragment (GSDME-N) and increasing phosphorylation level of MLKL. Additionally, 3m responds to pH/Viscosity. The present study describes a novel therapeutic 3m for the treatment of cancer, providing valuable insights into understanding the anticancer properties of these compounds.
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
·Vol. 24
·期 1
·184
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IF 15
Li Qingchen,Chen Lixue,Sun Yi,Wang Changyuan,Sun Yilun,Lu Kangjun,Li Lei,Sun Huijun,Liu Mozhen
PANoptosis, a distinct type of inflammation-associated programmed cell death that integrates features of apoptosis, necroptosis and pyroptosis, is closely related to the pathogenesis and progression of articular cartilage degeneration in osteoarthritis (OA). Meanwhile, excessive reactive oxygen species (ROS), pro-inflammatory pathways, and inflammatory cytokines in the OA microenvironment mutually reinforce one another, exacerbating synovial inflammation. To simultaneously target these interconnected pathological drivers, we developed an injectable nanocomposite thermosensitive hydrogel (DHA-PRO@NMs@TSH). This hierarchical system was constructed by integrating a ROS-responsive dihydroartemisinin prodrug (DHA-PRO) into Soluplus/TPGS-based nanomicelles (NMs), which were subsequently embedded within a Poloxamer-based thermosensitive hydrogel (TSH). This hierarchical and smart drug delivery system enables stable dihydroartemisinin (DHA) delivery and demonstrates a graded, ROS-triggered release profile, achieving sustained DHA retention in OA joints. The formulated system demonstrated excellent injectability, thermosensitivity, and physicomechanical stability, achieving sustained drug retention in rat joints for over 7 days, as confirmed by in vivo imaging. In vitro studies demonstrated that DHA-PRO@NMs significantly suppressed PANoptosis in chondrocytes by downregulating key markers (e.g., Bax/Bcl-2, RIPK3/p-RIPK3, NLRP3/Caspase-1/GSDMD) and inhibited inflammation by blocking the NF-κB pathway and subsequent cytokine production (e.g., TNF-α, IL-1β). In a rat OA model, treatment with DHA-PRO@NMs@TSH robustly attenuated disease progression, as evidenced by near-complete restoration of gait function, marked inhibition of cartilage degradation, a remarkable nearly 90% reduction in the Mankin score, and a comprehensive suppression of PANoptosis and inflammation pathological markers. This work not only presents a promising translational strategy for OA but also pioneers a therapeutic paradigm of leveraging advanced drug delivery system to dual-targeting PANoptosis and inflammation. Graphical abstract
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Advanced Healthcare Materials
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2026
·
IF 11
Ming Cheng,Jie Wu,Liru Heng,Yan Liu,Jinyu Yao,Tongtong Zhu,Yongming Zhu,Qiannan You,Zhubing Lei,Tong Wu,Wenfei Dong,Juan Yue,Yuanyuan Qin,Li Li
Glioblastoma (GBM) remains one of the most lethal intracranial malignancies due to its diffuse invasiveness and inevitable recurrence. Sonodynamic therapy (SDT) offers a noninvasive strategy for deep-tissue tumor ablation; however, its efficacy is often limited by rapid electron–hole recombination in conventional sonosensitizers, resulting in insufficient reactive oxygen species (ROS). In this study, a biomimetic nanosonosensitizer is rationally engineered via synergistic type II heterojunction interface construction and Cu─N coordination electronic activation. By anchoring Cu─N coordinated carbon dots (Cu-CDs) onto two-dimensional (2D) nanosheets, the compact heterojunction enables spatial charge separation, while Cu─N motifs act as kinetic promoters to accelerate interfacial electron transfer. This co-engineering strategy markedly enhances ultrasound (US) -triggered multi-ROS generation, leading to amplified oxidative stress. Biologically, intracellular copper overload triggers cuproptosis via lipoylated protein aggregation, whereas ROS burst induces PANoptosis-like cell death. Importantly, the synergistic death programs promote robust immunogenic cell death (ICD) with elevated Damage-associated molecular patterns (DAMPs) release/exposur, thereby activating antitumor immunity and contributing to enhanced therapeutic efficacy against GBM. This work provides new insights into the rational design of highly efficient sonosensitizers and offers new dimensions for precision SDT-based glioma sono-immunotherapy.
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BIOMATERIALS
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2025
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IF 12.9
Derui Xu,Tong Xu,Yunxiang Zhang,Yanjun Su,Xinmiao Hou,Yating Cui,Qian Liu,Lingxia Liu,Xiaotao Zhou,Haixu Xu,Xinghua Jin,Xichuan Li
Tumor immune microenvironment reconstruction and regulated cell death promotion synergistically enhance treatment outcomes in immunosuppressive non-small-cell lung cancer (NSCLC). PANoptosis, a newly identified form of immunogenic cell death that integrates the essential molecular components of pyroptosis, apoptosis, and necroptosis, elicits robust antitumor immunity via damage-associated molecular pattern (DAMP)-mediated immune activation. Nevertheless, strategies to induce PANoptosis remain underexplored, presenting a critical gap in leveraging its therapeutic potential. Herein, we engineered a multifunctional nanoreactor (Bi@SiO 2 @COP@AQ4N&PTX@hybrid-membrane, BSCAPM) as a PANoptosis inducer by integrating photothermal, photodynamic, chemotherapy, and SiO 2 -mediated biological effects. The nanoreactor features a bismuth-based core for photothermal functionality, in conjunction with a SiO 2 layer and a drug-loaded covalent organic polymer (COP) nanoplatform that synergistically disrupts mitochondrial homeostasis. In addition, the bioactive nanoparticles mediate co-delivery of paclitaxel and phenoxyanthraquinone, concurrently compromising nuclear DNA superhelical integrity and triggering profound mitochondrial stress culminating in PANoptosome assembly and ZBP1-dependent PANoptosis. In vitro and in vivo studies demonstrated that BSCAPM effectively targeted tumor sites, initiated ZBP1-dependent PANoptosis and elicited a robust immunogenic response, leading to enhanced tumor elimination and lung metastasis restraints. This study not only elucidates the mechanistic basis of BSCAPM-induced PANoptosis but also provides a new strategy for the precise treatment of NSCLC.
研究领域:
肿瘤学
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免疫治疗
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纳米医学
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细胞死亡机制
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生物医学工程
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癌症免疫学
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CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Zhechen Fan,Junqiu Ye,Sijia Yao,Zhongsheng Ji,Weisong Li,Jianping Zhou,Hao Cheng,Yang Ding
The efficient tumor ablation strategy accompanied with metastasis blocking is critical for triple-negative breast cancer (TNBC) therapy. Herein, we develop a cascade pH-responsive chemo-gene delivery nanosystem to actuate PANoptosis of tumor cells and suppress metastasis via bystander effect. Structurally, a charge reversal and acid-activated cell-penetrating peptide (CACPP) is covalently anchored onto GO surface, together with co-loading of doxorubicin (Dox) and TNBC-selective TRAIL expressing plasmid (pbTRAIL) onto GO surface via π-π stacking and calcium phosphate (CaP) biomineralization to yield nanosystem of Dox GPCaP pbTRAIL . After intravenous administration, the nanosystem could selectively accumulate at tumor site since CACPP modified nanosheet resurrects in tumor acidic microenvironment (Cascade 1). The internalized Dox GPCaP pbTRAIL nanosystem is further translocated into lysosome, where lower pH triggers burst drug release via Dox protonation and CaP dissolution (Cascade 2), followed with pbTRAIL liberation and lysosomal escape. The combination of Dox and TRAIL induces advanced apoptosis and necrosis of tumor cells; Meanwhile, GO-derived nanosheets share high photothermal conversion efficiency upon laser irradiation, thereby inducing pyroptosis and promoting PANoptosis synergistically. Our study demonstrates tumor-specific accumulation of Dox GPCaP pbTRAIL nanosystem and high capability of PANoptosis induction both in vitro and in vivo, yielding high tumor inhibition rate of 96 % and survival rate of 100 %. Collectively, the cascade pH-responsive multi-drug delivery nanosystem provides a novel approach for PANoptosis therapy of TNBC.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
·
IF 5.6
Fu-li Shi,Yang-feng Lv,Shi-qi Luo,Yu-xuan Sun,Xiang-qiong Wen,Yue-xiang Ren,Yu-xing Yang,Peng Yu,Qiong-feng Chen,Xian-he Yang,Shan Xu,Jie Qing,Dong-yun Ouyang,Jian-ming Li
Introduction PANoptosis, an inflammatory cell death pathway that integrates pyroptosis, apoptosis, and necroptosis, contributes critically to the pathogenesis of inflammatory diseases including hemophagocytic lymphohistiocytosis (HLH). However, the molecular regulation of PANoptosis and its pharmacological intervention remain poorly defined. Objectives This study aimed to investigate the regulatory role of XIAP in PANoptosis and to evaluate the therapeutic potential of luteolin, a natural flavonoid, as a pharmacological inhibitor of PANoptosis. Methods Murine macrophage models were used to assess PANoptosis induction and inhibition. Structural and biochemical approaches were applied to determine the interaction between luteolin and XIAP. Mitochondrial function, ROS accumulation, oxidized mitochondrial DNA, and z-DNA generation were examined, while autophagy was evaluated as a modulatory mechanism. Therapeutic efficacy was further validated in a poly(I:C)/LPS-induced HLH mouse model. Results XIAP was identified as an essential component of the PANoptosome complex, and its knockdown abolished PANoptosis formation. Luteolin directly bound to XIAP, destabilized its structure, and disrupted its interaction with PANoptosome, thereby blocking PANoptosome assembly. Luteolin preserved mitochondrial integrity, reduced ROS accumulation, and inhibited the generation of oxidized mtDNA and z-DNA. Importantly, luteolin enhanced autophagic clearance of damaged mitochondria by relieving XIAP-mediated suppression of autophagy. In vivo, luteolin treatment significantly attenuated systemic inflammation, protected organ function, and improved survival in HLH mice, effects associated with diminished PANoptosome formation and reduced z-DNA accumulation. Conclusions This study establishes XIAP as a central regulator of PANoptosis and demonstrates luteolin as a natural inhibitor targeting XIAP to block PANoptosome assembly and mitochondrial dysfunction. These findings provide a novel pharmacological strategy for treating PANoptosis-driven inflammatory diseases.
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JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Yue Zhang,Hongmin Lu,Lulu Hou,Xin Zhang,Tiantian Guo,Ruoqi Wang,Qi Wang,Mingwei Xing
Acetochlor is a widely used and highly effective herbicide. Its overuse poses significant threats to biosecurity and ecological integrity, particularly affecting free-ranging birds. Data on its impact, especially mechanisms of liver toxicity in chickens, are lacking. Thus, we established an animal-cell-animal model to explore intrinsic mechanisms at multiple levels. We found that acetochlor exposure caused liver cell swelling, inflammatory cell accumulation, and lipid deposition. Transcriptomic analyses revealed that differential gene were mainly enriched in hepatic immune, inflammatory, and programmed cell death pathways. We next focused on the gene GPR120, conducting transfection and agonism experiments in LMH, HD11, and co-cultured cells. Acetochlor significantly increased ROS accumulation, activated the NLRP3 inflammasome, and which induced PANoptosis. HD11 cells exhibited M1 polarization with upregulated pro-inflammatory factors. Silencing GPR120 exacerbated cellular damage and immune responses, whereas its agonist, GSK7A, dramatically reduced macrophage M1 polarization and mitigated immune damage to LMH cells. Finally, we returned to animal studies, adding Omega-3-a known GPR120 agonist-to the diet. Omega-3 effectively reversed acetochlor-induced hepatitis and PANoptosis. Given that acetochlor residues pose potential threats to ecosystems and avian health, it is crucial to strengthen residue control, conduct risk assessments, and explore targeted pathways and nutritional supplementation to counteract these negative impacts.
研究领域:
毒理学
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免疫学
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分子生物学
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兽医学
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PHYTOMEDICINE
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2025
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IF 8.3
Yiqiong Wang,Yi Tao,Shujing Zhang,Qiuru Wang,Zheting Liu,Shudong Lin,Yaoting Wang,Yunchao Huang,Ting Zhang,Henry Anselmo Mayala,Wenming He,Hui Shen,Ling Zhang,Hui Chai
Background Diabetes mellitus (DM) and its complications pose a significant threat to human health. Diabetes-related lower limb ischemia (DLLI), as a severe complication of diabetic macrovascular disease, presents substantial challenges in clinical management. Purpose The pharmacodynamic profile and mode of action of Pseudostellaria heterophylla polysaccharides (PHP) in DLLI treatment constitute the core investigative objectives herein. Study Design Using complementary in vivo (DLLI murine model) and in vitro (high glucose (HG)-exposed human umbilical vein endothelial cells (HUVECs)) systems, PHP's bioactivity was systematically profiled. Methods In vivo: The effects of PHP on blood perfusion, microvessel density, and PANoptosome assembly in the ischemic limbs of DLLI mice were evaluated. In vitro: HUVECs treated with HG were used to assess PHP’s regulatory effects on angiogenesis functions (cell migration, proliferation, tube formation), PANoptosome/inflammasome formation, key components of the PANoptotic pathway, reactive oxygen species (ROS/mtROS), mitochondrial homeostasis, and autophagy. Transcriptomic analysis was conducted to identify potential target genes. Results In vivo: PHP significantly improved blood perfusion, increased microvessel density, and modulated PANoptosome assembly in ischemic limbs. In vitro: PHP reversed HG-induced angiogenesis dysfunction, inhibited PANoptosis and oxidative stress, restored mitochondrial function, and enhanced autophagic activity. Mechanism: PHP exerted its effects by targeting cytochrome P450 enzyme CYP2E1 through downregulating its expression, thereby alleviating mitochondrial damage and PANoptosis. Additionally, CYP2E1 downregulation promoted endothelial cell migration. Conclusion We pioneered a PANoptosome-centric framework for DLLI, proving that PHP targets CYP2E1 to restore mitochondrial homeostasis, inhibit PANoptosis, and drive angiogenesis, thereby offering a novel natural product-derived therapeutic strategy. Collectively, this work establishes PHP as a promising candidate for DLLI treatment through CYP2E1-mediated restoration of mitochondrial homeostasis and PANoptosis suppression.
研究领域:
药理学
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内分泌学
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心血管研究
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分子生物学
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天然产物
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线粒体生物学
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细胞死亡机制
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