Science Advances
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2026
·Vol. 12
·期 25
·eaea6844
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IF 13.9
Jiaoting E,Yuxuan Zhao,Xiaoling Zhang,Qiuqi Zhang,Ying Xu,Shanshan Liu,He Ding,Jiuxin Zhu,Piaoping Yang,Rui Xie
Hepatocellular carcinoma (HCC) remains a challenge for therapeutic efficacy in converting cold tumors into hot ones. Herein, doping defect–engineered manganese perovskite piezoelectric nanocubes (Mn-BaZrO 3 , MBZO) integrated miltirone biomimetic delivery within tumor-derived nanovesicles are proposed for the parallel pyroptosis-apoptosis-necroptosis (PANoptosis) and the stimulator of interferon genes (STING) pathway activation to reshape the immune microenvironment, leading to tumor regression in HCC. Homologously targeting HCC cells, MBZO nanocubes accumulated and produced exogenous reactive oxygen species through the piezocatalytic effect. Specifically, miltirone accelerated oxidative stress amplification, potentially serving as an inducer of programmed cell death in HCC. Then, PANoptosis was activated to disrupt the cell barrier and release damage-associated molecular patterns, promoting immunogenicity. Concurrently, MBZO synergistically stimulated the STING pathway to evoke pro-inflammatory responses and elicit immunogenic cell death, triggering effector immune cell deployment (EICD). The piezobiomimetic delivery nanosystem bridged innate immunity activation and EICD to convert cold tumors into hot tumors and suppress tumor growth, thereby enhancing the efficacy of piezoimmunotherapy in HCC. A biomimetic nanomedicine activates PANoptosis and STING pathways to enhance the efficacy of liver cancer management.
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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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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2025
·
IF 9.7
Jiaxin Lin,Jingqi Chen,Minghao Li,Dan Li,Zheye Zhang,Peng Chen,Weiqing Zhang
Reactive oxygen species (ROS) are central regulators of redox homeostasis and cell fate. However, their precise orchestration to trigger PANoptosis, a coordinated form of programmed cell death (PCD) integrating pyroptosis, apoptosis, and necroptosis, remains underexplored. Herein, we report a gold single-atom nanozyme (Au-SA/NHC) featuring atomically dispersed Au N 4 sites that enable energy-independent, parallel and cascaded ROS generation. By mimicking peroxidase (POD), catalase (CAT), and glutathione oxidase (GSH-OXD) activities, Au-SA/NHC sustainably produces singlet oxygen ( 1 O 2 ) and hydroxyl radicals (∙OH) from endogenous substrates while depleting glutathione (GSH) to amplify oxidative stress. This redox remodeling triggers mitochondrial dysfunction, which acts as a central hub to bridge ROS stress with the assembly of the PANoptosome and activation of downstream signaling. Pharmacological and redox interventions—including ROS scavenging, mitochondrial protection, and inhibition of individual death modules—validated this axis and confirmed that PANoptosis represents the predominant cell death mode induced by Au-SA/NHC. In vivo, Au-SA/NHC significantly suppressed tumor growth with favorable biocompatibility, whereas ROS scavenging abolished therapeutic efficacy, underscoring the essential role of oxidative stress. Collectively, this work establishes a redox-engineered single-atom nanozyme as a next-generation catalytic nanotherapy capable of precisely engaging coordinated cell death programs through the ROS–mitochondria–PANoptosis axis.
研究领域:
肿瘤学
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纳米医学
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细胞死亡机制
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氧化还原生物学
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分子生物学
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转化医学
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生物材料
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BIOORGANIC CHEMISTRY
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2026
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IF 5.1
Yuting Liu,Tianyi Kang,Cuiping Shi,Fangfang Wei,Yixiu Zhong,Xin Hong,Jianglin Zhang,Kai Li
Exploring photosensitizers that efficiently generate oxygen-independent hydroxyl radical (•OH) and activate highly immunogenic PANoptosis and ferroptosis shows promise in addressing the limited efficacy of photodynamic immunotherapy (PDI) in the hypoxic and immunosuppressive tumor microenvironment (TME). However, challenges still exist due to the unsatisfactory •OH production efficiency in most organic photosensitizers and the unresolved relationship between •OH and PANoptosis. Here, we designed and synthesized two novel iridium(III) complexes, Ir1 and Ir2 . Notably, Ir1 produced more type I/II reactive oxygen species under light versus Ir2 and the clinically-used Chlorin e6 (Ce6), including a 25-fold higher •OH yield than both controls. Under extreme intracellular hypoxia, where superoxide anion (O 2 •- ) and singlet oxygen ( 1 O 2 ) were restricted, Ir1 maintained normoxia-equivalent •OH production, which endowed it with remarkable phototoxicity (IC 50 = 0.98 μM) and effective phototoxic index (PI = 3.05). Mechanistically, the •OH produced by Ir1 induced PANoptosis by increasing the expression of cleaved Caspase-3, GSDMD-N, and p-MLKL, and activated ferroptosis through the GSH-GPX4-LPO axis. Subsequently, Ir1 induced immunogenic cell death by enhancing the release of damage-associated molecular patterns under hypoxia, leading to a 1.8-fold increase in dendritic cell maturation. In melanoma-bearing mice, Ir1 achieved 89% reduction in tumor volume and transformed the immunosuppressed “cold” tumors to the inflamed “hot” phenotypes. This work establishes that the efficient •OH generation from iridium(III)-based photosensitizer can synergistically trigger PANoptosis and ferroptosis. This constitutes a viable approach for achieving effective PDI in hypoxic and immunosuppressive TME.
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Yonghu Chen,Linying Hu,Qiang Fu,Hongzhen Chen,Zhe Jiang,Xuezheng Li
Ethnopharmacological relevance Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by alveolar epithelial injury, inflammation, and excessive extracellular matrix deposition, yet current therapeutic options remain limited. Panax ginseng C.A. Meyer, a renowned qi-tonifying herb in traditional Chinese medicine, has long been used to enhance spleen and lung function by replenishing qi. However, the mechanism of action of its primary active component, ginseng stem and leaf saponins (GSLS), in pulmonary fibrosis remains incompletely understood. Aim of the study : This study aims to elucidate the protective role of GSLS against pulmonary fibrosis by investigating how GSLS regulates mitochondrial transcription factor A (TFAM)–mtDNA homeostasis and suppresses PANoptosis in alveolar epithelial cells. Materials and methods The major constituents of GSLS were identified using UHPLC–Q Exactive HFX. A BLM-induced mouse model of pulmonary fibrosis and an MLE-12–primary fibroblast co-culture system were established to evaluate the therapeutic effects of GSLS. Surface plasmon resonance (SPR) and cell thermal shift assays (CETSA) were performed to assess the direct interaction and thermal stability between GSLS and TFAM. Co-immunoprecipitation (Co-IP), RT-qPCR, and immunofluorescence were used to evaluate PANoptosome assembly, cytosolic double-stranded DNA (dsDNA) leakage, and fibrotic marker expression. Results GSLS was found to contain multiple active ginsenosides, including Rk2, CK, Rk3, and Rf. In vivo , GSLS markedly alleviated BLM-induced lung pathological injury, reduced collagen deposition, and decreased oxidative stress. In vitro , GSLS directly bound to TFAM and enhanced its thermal stability. RT-qPCR and immunofluorescence analyses further demonstrated that GSLS effectively suppressed abnormal cytosolic dsDNA leakage, reduced MLE-12 cell death, and ameliorated mitochondrial dysfunction. Moreover, GSLS inhibited the assembly of the PANoptosome complex, suppressed epithelial PANoptosis, and decreased the expression of fibrosis-related proteins. Conclusion GSLS mitigates BLM-induced pulmonary fibrosis by stabilizing TFAM, maintaining mtDNA homeostasis, and suppressing PANoptosis. This clarifies the potential mechanism of GSLS therapy for PF.
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Materials Today Bio
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2025
·
IF 10.2
Yanhui Cui,Xueqin Wang,Caiyang Lu,Liling Ran,Zirui Guo,Jiayu Yao,Tian Yu,Xuanxi Liu,Fang Li,Changqi Li,Yingcai Meng,Wenhu Zhou
Acute lung injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) is a life-threatening condition marked by severe inflammatory responses and disruption of the alveolar-capillary barrier, leading to high mortality rates and lack of effective treatments. Recent research has underscored the crucial role of programmed cell death pathways-pyroptosis, apoptosis, and necroptosis-in exacerbating inflammation and barrier dysfunction in ALI/ARDS. However, effective therapeutic agents targeting this process remain scarce. In this study, we reveal that PANoptosis, which integrates these cell death pathways through the PANoptosome complex, plays a central role in the pathogenesis and progression of ALI/ ARDS. The levels of PANoptosis-related molecules were significantly elevated in both the ALI mice and the clinical ARDS patient samples, highlighting it as a novel therapeutic target. Building on this insight, we developed a multifunctional nanomedicine, TPNs/Sal B, which integrates tea polyphenol-based nanoparticles (TPNs), a bioactive nanomaterial with anti-pyroptotic and anti-necroptotic properties, with salvianolic acid B (Sal B), known for its anti-apoptotic effects. Our results demonstrate that the nanomedcine TPNs/Sal B effectively inhibit PANoptosis, thereby attenuating lung tissue pathological damage, reducing inflammation, and improving lung epithelial barrier function in ALI models. Moreover, we identified LIM and SH3 protein 1 (LASP1) which may play an critical role in modulating alveolar epithelial barrier function during ALI/ARDS progression, and treatment with TPNs/Sal B effectively restored LASP1 levels. Our findings underscore the therapeutic potential of TPNs/Sal B as a targeted treatment for ALI/ARDS, offering a promising strategy for modulating PANoptosis and preserving lung function.
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SCIENCE OF THE TOTAL ENVIRONMENT
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2023
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IF 9.8
Quanwei Li,Pan Guo,Shaofeng Wang,Luna Su,Tingyu Liang,Wenlan Yu,Jianying Guo,Qingwen Yang,Zhaoxin Tang,Jianzhao Liao
Terbuthylazine (TBA) is a widely prevalent pesticide pollutant, which is a global concern due to its environmental residual. However, the toxic mechanism of TBA have not been fully solved. Here, we explored that TBA exposure disrupts the intestinal flora and aggravated disturbance of mitochondrial quality control and PANapoptosis in hepatocytes via gut-liver axis. Our findings demonstrated that TBA exposure induced significant damage to the jejunum barrier, evidenced by a marked decrease in the expression of Occludin and ZO-1. Moreover. TBA led to intestinal microflora disorder, manifested as the decreased abundance of Firmicutes , and increased abundance of the Nitrospirota , Chloroflexi , Desulfobacterota , Crenarchaeota , Myxococcota , and Planctomycetota . Meanwhile, intestinal microflora disorder affected the biological processes of lipid metabolism and cell growth and death of hepatocytes by RNA-Seq analysis. Furthermore, TBA could induced mitochondrial quality control imbalance, including mitochondrial redox disorders, lower activity of mitochondrial fusion and biogenesis decrease, and increasing level of mitophagy. Subsequently, TBA significantly increased expression levels of pyroptosis, apoptosis and necroptosis-related proteins. In general, these results demonstrated the underlying mechanisms of TBA-induced hepatotoxicity induced via the gut–liver axis, which provides a theoretical basis for further research of ecotoxicology of TBA.
研究领域:
毒理学
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环境科学
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分子生物学
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胃肠病学
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肝病学
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JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Xiaoping Xie,Kexin Wang,Xiaoyan Shen,Xu li,Su Wang,Shun Yuan,Bowen Li,Zhiwei Wang
Microplastics (MPs) have attracted widespread attention because they can lead to combined toxicity by adsorbing heavy metals from the environment. Exposure to lead (Pb), a frequently adsorbed heavy metal by MPs, is common. In the current study, the coexistence of MPs and Pb was assessed in human samples. Then, mice were used as models to examine how co-exposure to MPs and Pb promotes aortic medial degeneration. The results showed that MPs and Pb co-exposure were detected in patients with aortic disease. In mice, MPs and Pb co-exposure promoted the damage of elastic fibers, loss of vascular smooth muscle cells (VSMCs), and release of inflammatory factors. In vitro cell models revealed that co-exposure to MPs and Pb induced excessive reactive oxygen species generation, impaired mitochondrial function, and triggered PANoptosome assembly in VSMCs. These events led to PANoptosis and inflammation through the cAMP/PKA-ROS signaling pathway. However, the use of the PKA activator 8-Br-cAMP or mitochondrial ROS scavenger Mito-TEMPO improved, mitochondrial function in VSMCs, reduced cell death, and inhibited inflammatory factor release. Taken together, the present study provided novel insights into the combined toxicity of MPs and Pb co-exposure on the aorta. Environmental Implication Microplastics (MPs) and Lead (Pb) are pervasive in the environment, yet studies on the cardiovascular toxicity of MPs and Pb co-exposure remain scarce. This research investigates the effects of MPs and Pb co-exposure on aortic medial degeneration (AMD). The findings reveal the presence of MPs and Pb exposure in patients. Co-exposure to MPs and Pb accelerates AMD in the mice. Further experiments confirm that co-exposure to MPs and Pb affects vascular smooth muscle cell activity and inflammation by regulating the cAMP/PKA pathway and mitochondrial function. Our study offers new insights into the synergistic toxic mechanisms of MPs and Pb.
研究领域:
环境科学
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毒理学
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心血管疾病
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Theranostics
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2026
·Vol. 16
·期 2
·830
·
IF 13.3
Shuhan Meng,Weizhou Fang,Yukun Wu,Zhaohua Xia,Tiansheng Chou,Yang Xia,Lexi Ding,Xuezhi Zhou,Xiaobo Xia
Rationale: Acute glaucoma is triggered by sudden spikes in intraocular pressure, which induces retinal ischemia/reperfusion (RI/R), leading to hypoxia, oxidative stress, and ultimately PANoptosis in retinal ganglion cells (RGCs). Developing a therapeutic approach that simultaneously targets these events may offer a promising strategy for reducing secondary neuronal damage in acute glaucoma. Methods: We developed a reactive oxygen species (ROS)/hypoxia dual-responsive, biodegradable nanoparticle system (NPs) containing azo and thioketal bonds, designed to encapsulate melatonin (MT), a known endogenous antioxidant and PANoptosis inhibitor. The biocompatibility, biosafety, and therapeutic efficacy of MT-NPs were evaluated in vitro using an oxygen-glucose deprivation/reperfusion (OGD/R) R28 cell model and in vivo using a RI/R rat model. Results: The NPs efficiently released encapsulated MT in response to hypoxic conditions and the presence of ROS. This controlled-release system improved both the biocompatibility and long-term retention of MT in the retina. MT-NPs effectively alleviated hypoxia, cleared excess ROS, and inhibited PANoptosis in RGCs following acute glaucomatous injury. Compared to direct MT administration, MT-NPs were more effective at protecting RGC axons and somas and facilitating restoration of visual function in rats with acute glaucoma. Conclusion: This simplified but multifunctional delivery system leveraged the widely available and safe compound melatonin in a highly efficient nanoparticle platform. This system offers potent neuroprotective effects to the retina preventing injury caused by acute glaucoma, and thereby providing a promising clinically translatable strategy for the treatment of glaucoma.
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Advanced Science
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2026
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IF 14.1
Yao Xiao,Yuxuan Yang,Haosen Qiu,Jia Yang,Hao Liang,Zhaojun Jiang,Xiao Tong,Yongying Li,Qunfeng Huang,Jiaming Wu,Tian Lin,Jiang Yu,Min Liang
Colorectal cancer (CRC) remains therapeutically challenging due to high metastasis, recurrence, and immunotherapy resistance driven by tumor microenvironment-mediated immune evasion. Immunogenic cell death (ICD) offers a promising strategy to reshape the immune microenvironment, yet existing ICD inducers suffer from poor targeting efficiency and insufficient death signal release. Here, we constructed a calcium overload-based smart nanosystem, HA-HAP@CUR, to achieve highly efficient ICD induction via a triple-effect mechanism: hyaluronic acid (HA)-mediated CD44 targeting enables tumor-selective accumulation; pH-responsive hydroxyapatite (HAP) degradation releases Ca 2+ in the acidic tumor microenvironment; and curcumin (CUR) amplifies intracellular calcium overload by promoting endoplasmic reticulum Ca 2+ release, collectively establishing a positive feedback loop disrupting calcium homeostasis. Mechanistically, calcium overload induces mitochondrial membrane potential dissipation and sustained mPTP opening, triggering mitochondrial oxidative stress and energy metabolic disorders. This mitochondrial crisis concurrently activates caspase-3, GSDMD, and RIPK1, synergistically initiating apoptosis, pyroptosis, and necroptosis, ultimately converging into PANoptosis with potent immunostimulatory potential. This strategy, encompassing targeted accumulation, calcium storm activation, and multi-modal cell death synergy, provides a biologically precise approach to overcoming immunotherapy resistance in CRC.
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JOURNAL OF CONTROLLED RELEASE
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2026
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IF 12.4
Kexin Wen,Chenxi Zhang,Qin Fan,Jinqiao Zhang,Yuhan Mo,Junjun Huang,Songling Liu,Xin Wang,Ziliang Dong
PANoptosis, an inflammatory cell death integrating pyroptosis, apoptosis, and necroptosis, has emerged as a promising approach for tumor immunotherapy. Reactive oxygen species (ROS) generation is the predominant strategy for triggering PANoptosis. However, in solid tumors, the hypoxic microenvironment suppresses ROS production, thereby limiting PANoptosis induction. Herein, we present an in situ-formed pH-responsive injectable hydrogel enabling sequential delivery of 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) and Type I sonodynamic nanoparticles for hypoxic tumor immunotherapy. Upon intratumoral injection, the hydrogel gradually degrades in acidic conditions. DMXAA is released first, inducing vascular shutdown and aggravating tumor hypoxia. Subsequently, nanoparticles are liberated and, under ultrasound, generate abundant ROS via a Type I sonodynamic process, bypassing oxygen dependence. The ROS burst triggers tumor cell PANoptosis, leading to immunogenic cell death, promoting antigen release and dendritic cell maturation. In multiple hypoxic tumor models, this sequential approach achieved significant tumor regression, suppressed metastasis, and induced durable immune memory to prevent recurrence. Overall, our work presents an injectable hydrogel platform that integrates controlled drug release, Type I sonodynamic PANoptosis, and immune activation for enhanced antitumor immunotherapy.
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JOURNAL OF NUTRITIONAL BIOCHEMISTRY
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2026
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IF 5.2
Yuting Dong,Xiaodan Wang,Shize Wang,Kang Yang,Tong Xu,Hongjin Lin
DEHP induces thymus injury in chickens by activating the NF-κB/TNF-α pathway, triggering oxidative stress and PANoptosis. • QUE can alleviate the activation of the NF-κB/TNF-α pathway, oxidative stress and PANoptosis induced by DEHP in chickens. • QUE exerts a targeted effect on NF-κB, thereby mitigating DEHP-induced thymus injury in chickens. Quercetin (Que), a natural dietary flavonoid, possesses significant antioxidative and immunoregulatory properties. Di(2-ethylhexyl) phthalate (DEHP), a pervasive environmental endocrine-disrupting chemical, triggers oxidative stress (OS) and elicits immunotoxic effects in various species. However, whether Que can target NF-κB to alleviate DEHP-induced OS and PANoptosis in the chicken thymus remains unclear to date. To investigate the mechanism of thymus damage induced by DEHP and the intervention effect of Que, we established an in vivo chicken model treated with DEHP and/or Que. Based on the results of network pharmacology, molecular docking, molecular dynamics simulations, and Cell Thermal Shift Assay (CETSA), we predicted that NF-κB is the key target for the protective effect of Que. Subsequently, through H&E staining, CCK-8, immunofluorescence, Western blot and other techniques, we verified the effects of DEHP and/or Que on OS, the assembly of PANoptosome, and cellular PANoptosis in chicken thymus tissue and chicken lymphocyte cell line (MSB-1). Meanwhile, to clarify the key role of NF-κB in the above regulatory process, we conducted reverse validation experiments by introducing the NF-κB activator Act1 in cellular experiments. The results demonstrated that DEHP exposure markedly induces the upregulation of NF-κB and TNF-α(P<0.05), leading to a pronounced burst of reactive oxygen species (ROS) and consequent OS within the chicken thymus. This process further activates the ZBP1-mediated PANoptosis pathway, ultimately causing damage to chicken thymus tissue. Que intervention effectively suppresses NF-κB activation, blocking the transmission of the NF-κB/TNF-α/ROS signaling axis, thereby reversing DEHP-induced ZBP1-mediated PANoptosis in chicken thymus. Download: Download high-res image (290KB) Download: Download full-size image
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