Cancers
·
2025
·Vol. 18
·期 1
·92
·
IF 4.4
Hao Dong,Yuan Gao,Dongyue Jiang,Chenjie Feng,Xinyue Gu,Xiyunyi Cai,Yulin Liu,Guangyu Zhang,Jiacheng Wen,Weiwei Diao,Ying Zhou,Ruixin Li,Dayang Xu,Weijia Xie,Liang Wu
Simple SummaryHepatocellular carcinoma (HCC) is characterized by high incidence and mortality rates, yet effective therapeutic drugs remain scarce, creating an urgent need for viable treatment strategies. This study aimed to develop novel small-molecule anti-HCC agents based on the naturally derived antitumor compound caffeic acid phenethyl ester (CAPE), evaluate their efficacy against HCC, and investigate their underlying pharmacological mechanisms. A total of 28 structurally analogous small-molecule derivatives were synthesized, from which the most potent compound, designated WX006, was selected. Using an integrated approach encompassing molecular biology, cell biology, computational biology, and multi-omics analysis, we demonstrated that WX006 effectively depletes Nicotinamide adenine dinucleotide (NAD+) in HCC cells by binding to NADH: Ubiquinone Oxidoreductase Core Subunit S2 (NDUFS2), thereby disrupting mitochondrial function and intracellular metal ion homeostasis. This study provides valuable and independent insights into the development of derivatives based on the natural small molecule CAPE and establishes a further foundation for the advancement of anti-HCC therapies.Background: In this study, 28 caffeic acid phenethyl ester (CAPE) derivatives were designed and synthesized, and their anti-proliferative activities were evaluated against two representative human hepatocellular carcinoma (HCC) cell lines. The half-maximal inhibitory concentration (IC50) was used as the activity metric. Among these derivatives, compound WX006 displayed the most potent anti-proliferative effect, with IC50values of 3.332 μM and 3.764 μM after 48 h of treatment, significantly lower than those of the parent compound CAPE. Consequently, WX006 was selected for further investigation into its antitumor efficacy and underlying mechanisms. Methods: To investigate the pharmacological mechanism of WX006, we employed a combination of high-throughput transcriptomics, metabolomics, and mitochondrial function analysis to elucidate its intracellular mechanisms of action. Results: WX006 disrupts cytoplasmic-mitochondrial metal ion homeostasis, triggering ferroptosis and cuproptosis through iron-copper dysregulation. Computational modeling revealed that WX006 selectively inhibits mitochondrial NDUFS2 subunit of respiratory chain complex I, which may induce NAD+exhaustion and consequent energy metabolism collapse in tumor cells. These “metabolism & metal homeostasis” dual mechanisms collectively underpin its robust anti-tumor effects. Therapeutic efficacy of WX006 was further validated in murine H22 ectopic xenograft and Hepa1-6-Luc orthotopic xenograft models, where WX006 exhibited superior tumor suppression compared to sorafenib, alongside favorable safety profiles. Conclusions: Our findings establish a foundational rationale for further pharmaceutical development of CAPE derivates as a promising therapeutic candidate for hepatocellular carcinoma.
研究领域:
肿瘤学
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药物化学
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分子生物学
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癌症药理学
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代谢组学
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计算生物学
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2026
·
IF 5.9
Shengnan Huang,Weiwei Zhi,Mengjie Zhao,Gaojian Wei,Manyu Zhang,Yu Chen,Yijing Li,Lihua Cao,Jingyi Qiao,Yurong Hu,Hui Zhao,Mingsan Miao,Xiali Zhu
To exploit the therapeutic synergy of nanoparticle-induced calcium overload and oxidative stress dysregulation, we developed a core-shell nanoplatform, termed CK@PTM (comprising kaempferol-loaded calcium peroxide nanoparticles coated with a PEG-tannic acid/manganese metal-phenolic network), to amplified therapeutic efficacy against breast cancer. Structurally, kaempferol (KAE)-loaded calcium peroxide (CaO₂) nanoparticles served as the functional core, subsequently enveloped by a dual-responsive metal-phenolic network (MPN) formed through Mn²⁺coordination with polyethylene glycol-modified tannic acid (PEG-TA). This hierarchical architecture enabled pH/glutathione (GSH) dual-responsive payload co-release, facilitated by acid-triggered CaO₂ dissolution concurrent with pH/GSH- triggered MPN decomposition. Critically, CK@PTM orchestrated a severe redox imbalance via concomitant GSH depletion and reactive oxygen species (ROS) burst, thereby amplifying tumoricidal activity. Cellular uptake assays revealed efficient CK@PTM internalization into breast cancer cells, potentially attributable to TA-enhanced membrane affinity. Both in vitro and in vivo evaluations demonstrated significant tumor growth suppression of CK@PTM, driven primarily by the synergistic reciprocal potentiation of KAE-augmented Ca²⁺ overload and nanoplatform-induced oxidative stress. Furthermore, CK@PTM triggered immunogenic cell death (ICD), as evidenced by damage-associated molecular pattern (DAMP) release, suggesting potential for activating T-cell-mediated antitumor immunity. Collectively, this nanotherapeutic strategy established a proof-of-concept paradigm for bidirectional amplification of calcium-overload and oxidative-stress signaling cascades, presenting a promising approach for solid tumors.
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ACS Nano
·
2026
·
IF 17.3
Yang Chen,Ranjie Lei,Qi Guo,Kehao Liu,Huaiyi Cheng,Sanyang Yu,Yuzhou Li,Ping He,Sheng Yang
Cationic materials serve as a critical strategy for capturing neutrophil extracellular traps (NETs), which are structured around negatively charged DNA and represent a key pro-inflammatory pathogenic factor. However, their application is constrained by the inherent cytotoxicity of positive charges. Here, we develop a charge-adaptive neutrophil-targeted nanoparticle system (CPS@BA) through conjugating sialic acid (SA) to carboxymethyl chitosan (CMCS)–polyethylenimine (PEI) copolymer and physically encapsulating the calcium chelator BAPTA-AM (BA). This smart nanoparticle exhibits charge adaptability, dynamically and reversibly responding to acidic transitions in the pathological milieu. When sensing the acidic milieu on activated neutrophil surfaces, CPS@BA reverses its charge from negative to positive, thereby facilitating rapid NETs capture. Once inflammation is resolved and the pH returns to neutral, the residual CPS@BA reversibly switches back to biocompatible negative charges, effectively minimizing cationic biotoxicity. Meanwhile, charge adaptation triggers a cascade of size adaptation, enabling CPS@BA to ingeniously regulate the release of BA, which could suppress further NETs formation by chelating intracellular Ca2+ and inhibiting PAD4 enzymatic activation. As a result, the simultaneous clearance and inhibition of NETs effectively block the detrimental crosstalk between NETs and macrophages by interrupting the CXCL3–CXCR2 axis. This intervention rescues mitochondrial dysfunction and promotes metabolic reprogramming in pro-inflammatory macrophages, ultimately alleviating inflammatory bone resorption in experimental periodontitis. Overall, this study presents a secure and reversible charge-adaptive strategy capable of simultaneously clearing and inhibiting NETs, holding broad potential for the treatment of all free DNA-driven inflammatory diseases.
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Acta Pharmaceutica Sinica B
·
2025
·
IF 14.6
Qian Jing,Mengnan Zhao,Yan Tang,Tao Chen,Mingyan Sun,Dandan Mi,Lan Zou,Rujing Wang,Jun Lu,Sanjun Shi
Interference with calcium homeostasis provokes tumor cell death and immune response, providing a novel direction for tumor immunotherapy as a promising cancer treatment strategy. Nevertheless, most reported Ca 2+ -overloaded nanoinducers encounter challenges such as intricate preparation procedures, safety concerns arising from inorganic material input, and limited anti-tumor efficiency. Herein, we synthesized a biocompatible and pH-sensitive Ca-doped cyclodextrin metal-organic framework (Ca/K-MOF) as a carrier, which was then loaded with photosensitizer hypericin (HY) via a simple one-pot synthesis to form HY@Ca/K-MOF. To enhance the stability both in vitro and in vivo , we coated HY@Ca/K-MOF with a hydrophilic layer of PEG ( PEG HY@Ca/K-MOF). When exposed to 590 nm photoirradiation, PEG HY@Ca/K-MOF, with its pH-responsive dissociation, the Ca 2+ and HY mediators released at the tumor site share the responsibility of triggering intracellular Ca 2+ disturbances, which amplified the production of reactive oxygen species (ROS) and led to mitochondrial calcium overload through modulating mitochondrial MICU1 function. Under photocontrol, this interplay between ROS generation and mitochondrial calcium overload created a bidirectional amplification effect, where each process reinforced the other, subsequently eliciting a pyroptosis-evoked immune response. Significantly, this newly constructed delivery platform effectively suppressed both primary and distant tumors without the need for additional immunological interventions. In summary, this Ca 2+ -doped MOF-based nanomaterial provides a promising approach for efficient tumor photo-controlled mitochondrial Ca 2+ overload-pyroptosis immunotherapy.
研究领域:
纳米医学
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癌症免疫治疗
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生物无机化学
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光动力治疗
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分子生物学
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药物递送系统
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Advanced Healthcare Materials
·
2026
·
IF 9.6
Xueqi Liang,Zhen Liu,Nan Wang,Xiao-kun Ouyang,Junhong Ling
Immunogenic cell death (ICD) induced by calcium overload holds great promise for reversing the immunosuppressive tumor microenvironment (TME) and improving cancer immunotherapy. However, achieving sustained calcium dysregulation remains a major challenge. Herein, we report a novel nanoplatform, termed Ca@CMPN, which co-delivers calcium hydride and curcumin using a mesoporous polydopamine carrier for synergistic ion-interference and gas immunotherapy. Upon encountering the acidic TME, Ca@CMPN disintegrates to release Ca 2+ , initiating intracellular calcium overload, and concurrently generates hydrogen gas (H 2 ). Crucially, the co-released curcumin acts from within the cell, amplifying the calcium overload by disrupting organellar calcium homeostasis, thereby ensuring robust ICD. Meanwhile, H 2 serves as a potent immunoadjuvant to alleviate oxidative stress and remodel the immunosuppressive TME. Both in vitro and in vivo studies demonstrate that Ca@CMPN effectively inhibits tumor growth and reprograms the TME, as evidenced by enhanced dendritic cell maturation, activation of cytotoxic T cells, and elevated levels of pro-inflammatory cytokines (interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α)). This work presents a paradigm-shifting strategy that synergizes ion-interference therapy with hydrogen immunotherapy, offering a powerful nanoplatform to unlock the full potential of cancer immunotherapy.
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Biomaterials Advances
·
2026
·
IF 6
Mao Tang,Laixian Zhou,Haitao Ran
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon characterized by recurrent mucosal inflammation and ulceration. Since managing UC remains challenging due to frequent therapeutic resistance and relapse, there is a pressing need for new strategies that target the underlying disease mechanisms to achieve long-term remission. Recent studies have highlighted the functional heterogeneity of intestinal goblet cells (GCs) beyond their classical role in mucus secretion. The goblet cell–associated passages (GAPs) have been identified as a luminal antigen delivery to lamina propria immune cells. Excessive GAP opening contributes to barrier dysfunction and mucosal inflammation, suggesting that GAPs are a promising therapeutic target. In this study, we designed a chondroitin sulfate–coated cerium nanoplatform (CS/CeO₂) loaded with the BAPTA-AM (BA) to stabilize the barrier function in colon. Briefly, BA was used to suppress excessive GAPs opening during the early stage of colitis, thereby alleviating abnormal immune activation. At the same time, CeO₂ served as a carrier to restrict the free diffusion of BA. Meanwhile, CS enabled efficient targeting of ulcerative lesions, allowing CeO₂ to fully exert its reactive oxygen species (ROS)–scavenging and CT imaging capabilities. Upon oral administration, BA-CS/CeO₂ successfully inhibited aberrant GAPs opening in DSS-induced colitis mice and enhanced intestinal barrier integrity, with restoration of mucus layer thickness and epithelial tight junctions, alongside reduced immune cell infiltration. Overall, this work leverages GC heterogeneity to re-establish intestinal barrier homeostasis, offering a promising nanotherapeutic strategy for UC through GAPs regulation, ROS scavenging, and CT monitoring.
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ACS Nano
·
2021
·
IF 15.881
Bin Liu,Yulong Bian,Shuang Liang,Meng Yuan,Shuming Dong,Fei He,Shili Gai,Piaoping Yang,Ziyong Cheng,Jun Lin
Recently, various metal peroxide nanomaterials have drawn increasing attention as an efficient hydrogen peroxide (H2O2) self-supplying agent for enhanced tumor therapy. However, a single kind of metal peroxide is insufficient to achieve more effective antitumor performance. Here, a hyaluronic acid modified calcium and copper peroxides nanocomposite has been synthesized by a simple one-step strategy. After effective accumulation at the tumor site due to the enhanced permeability and retention (EPR) effect and specific recognition of hyaluronate acid with CD44 protein on the surface of tumor cells, plenty of Ca2+, Cu2+, and H2O2 can be simultaneously released in acid and hyaluronidase overexpressed tumor microenvironment (TME), generating abundant hydroxyl radical through enhanced Fenton-type reaction between Cu2+ and self-supplying H2O2 with the assistance of glutathione depletion. Overloaded Ca2+ can lead to mitochondria injury and thus enhance the oxidative stress in tumor cells. Moreover, an unbalanced calcium transport channel caused by oxidative stress can further promote tumor calcification and necrosis, which is generally defined as ion-interference therapy. As a result, the synergistic effect of Fenton-like reaction by Cu2+ and mitochondria dysfunction by Ca2+ in ROS generation is performed. Therefore, a TME-responsive calcium and copper peroxides nanocomposite based on one-step integration has been successfully established and exhibits a more satisfactory antitumor efficiency than any single kind of metal peroxide.
研究领域:
癌症治疗
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纳米技术
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材料科学
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生物化学
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CELL CALCIUM
·
2018
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IF 3.718
Bin Liu,Wanxin Cao,Jiping Li,Jun Liu
Adenosine triphosphate (ATP) is stored as lysosomal vesicles in marginal cells of the stria vascular in neonatal rats, but the mechanisms of ATP release are unclear. Primary cultures of marginal cells from 1-day-old Sprague–Dawley rats were established. P2Y 2 receptor and inositol 1,4,5-trisphosphate (IP3) receptor were immunolabelled in marginal cells of the stria vascular. We found that 30 μM ATP and 30 μM uridine triphosphate (UTP) evoked comparable significant increases in the intracellular Ca 2+ concentration ([Ca 2+ ] i ) in the absence of extracellular Ca 2+ , whereas the response was suppressed by 100 μM suramin, 10 μM 1-(6-(17β-3-methoxyester-1,3,5(10)-trien-17-yl)amino)-hexyl)-1H-pyrrole-2,5-dione(U-73122), 100 μM 2-aminoethoxydiphenyl borate (2-APB) and 5 μM thapsigargin (TG), thus indicating that ATP coupled with the P2Y 2 R-PLC-IP3 pathway to evoke Ca 2+ release from the endoplasmic reticulum (ER). Incubation with 200 μM Gly-Phe-β-naphthylamide (GPN) selectively disrupted lysosomes and caused significant increases in [Ca 2+ ] I ; this effect was partly inhibited by P2Y 2 R-PLC-IP3 pathway antagonists. After pre-treatment with 5 μM TG, [Ca 2+ ] i was significantly lower than that after treatment with P2Y 2 R-PLC-IP3 pathway antagonists under the same conditions, thus indicating that lysosomal Ca 2+ triggers Ca 2+ release from ER Ca 2+ stores. Baseline [Ca 2+ ] i declined after treatment with the Ca 2+ chelator 50 μM bis-(aminophenolxy) ethane- N , N , N ʹ, N ʹ-tetra-acetic acid acetoxyme-thyl ester (BAPTA-AM) and 4 IU/ml apyrase. 30 μM ATP decrease of the number of quinacrine-positive vesicles via lysosome exocytosis, whereas the number of lysosomes did not change. However, lysosome exocytosis was significantly suppressed by pre-treatment with 5 μM vacuolin-1. Release of ATP and β-hexosaminidase both increased after treatment with 200 μM GPN and 5 μM TG, but decreased after incubation with 50 μM BAPTA-AM, 4 IU/ml apyrase and 5 μM vacuolin-1. We suggest that ATP triggers Ca 2+ release from the ER, thereby contributing to secretion of lysosomal ATP via lysosomal exocytosis. Lysosomal stored Ca 2+ triggers Ca 2+ release from the ER directly though the IP3 receptors, and lysosomal ATP evokes Ca 2+ signals indirectly via the P2Y 2 R-PLC-IP3 pathway.
研究领域:
细胞生物学
·
神经科学
·
生理学
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高影响因子
CHEMISTRY & BIODIVERSITY
·
2022
·Vol. 19
·期 9
·e202200447
·
IF 2.745
Ling Guo,Yanling Jin,You Yang,Jing Liu,Chunyan Liu,Yan Zeng,Qulian Guo,Wenjun Liu
Purple sweet potato is considered an abundant, inexpensive, and ideal source of anthocyanins. Purple sweet potato anthocyanins (PSPAs) have been shown to possess high antimutagenicity and antitumor effects due to the abundance of acylated anthocyanins. However, the effect and underlying mechanism of PSPA effects in acute lymphoblastic leukemia (ALL), especially T-cell acute lymphoblastic leukemia (T-ALL), remain unclear. In this study, the antileukemic effects of PSPAs and the underlying molecular mechanisms were evaluated by in vitro and in silico assays. PSPAs extracted from ten cultivars were analyzed and quantified. Anthocyanins from Nanzi 018, which showed the best antileukemic effect, were selected to analyze the underlying mechanism. First, the PSPAs potently reduced cell viability and induced apoptosis. Additionally, the PSPAs sharply increased intracellular Ca 2+ levels, which resulted in calcium overload in T-ALL cells. Furthermore, on the basis of bioinformatics analyses, we focused on an osmotically regulated transcription factor, NFAT5. Molecular docking preliminarily indicated that PSPA molecules bound and interacted with the NFAT5 protein. Western blot analyses confirmed that PSPAs elicited calcium overload by nonosmotic regulation of NFAT5/S100A4-S100A9 pathway activation. Moreover, pretreatment with a NFAT5 inducer confirmed that PSPAs targeted NFAT5 and affected p38/NF-κB/Bcl-2/Caspase-3 axis activation. This study demonstrates that PSPAs exert their antileukemic effects through calcicoptosis induction by targeting NFAT5.
研究领域:
肿瘤学
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药理学
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分子生物学
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生物化学
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高影响因子
Frontiers in Physiology
·
2023
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IF 4
Jiqiang Song,Yanping Yu,Zhichao Yan,Shan Xiao,Xianxin Zhao,Fang Wang,Qi Fang,Gongyin Ye
Chloride intracellular channel (CLIC) is a member of the chloride channel protein family for which growing evidence supports a pivotal role in fundamental cellular events. However, the physiological function of CLIC in insects is still rarely uncovered. The ovary-derived High Five (Hi-5) cell line isolated from the cabbage looper ( Trichoplusia ni ) is widely used in laboratories. Here, we studied both characteristics and functions of CLIC in Hi-5 cells ( Tn CLIC). We identified the TnCLIC gene in Hi-5 cells and annotated highly conserved CLIC proteins in most insect species. After RNA interference of TnCLIC , the phenomenon of significantly increased cell death suggests that the Tn CLIC protein is essential for the survival of Hi-5 cells. The same lethal effect was also observed in Spodoptera frugiperda 9 and Drosophila melanogaster Schneider 2 cells after CLIC knockdown. Furthermore, we found that this kind of cell death was accompanied by increases in intracellular calcium ions after TnCLIC knockdown with the transcriptomic analyses and the detection of calcium levels. Our results provide insights into insect CLIC as a key factor for cell survival and lay the foundation for the cell death mechanism.
研究领域:
分子生物学
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细胞生物学
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昆虫学
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遗传学
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 14
·11554
·
IF 5.6
Chehao Lee,Guang Xin,Fan Li,Chengyu Wan,Xiuxian Yu,Lijuan Feng,Ao Wen,Yu Cao,Wen Huang
Ninjurin 1 (NINJ1) is a double-transmembrane cell-surface protein that might mediate plasma membrane rupture (PMR) and the diffusion of inflammatory factors. PMR is a characteristic of acinar cell injury in severe acute pancreatitis (SAP). However, the involvement of NINJ1 in mediating the PMR of acinar cells in SAP is currently unclear. Our study has shown that NINJ1 is expressed in acinar cells, and the expression is significantly upregulated in sodium-taurocholate-induced SAP. The knockout of NINJ1 delays PMR in acinar cells and alleviates SAP. Moreover, we observed that NINJ1 expression is mediated by Ca2+concentration in acinar cells. Importantly, we found that Ca2+overload drives mitochondrial stress to upregulate the P53/NINJ1 pathway, inducing PMR in acinar cells, and amlodipine, a Ca2+channel inhibitor, can reduce the occurrence of PMR by decreasing the concentration of Ca2+. Our results demonstrate the mechanism by which NINJ1 induces PMR in SAP acinar cells and provide a potential new target for treatment of SAP.Keywords:nerve-injury-induced protein 1;plasma membrane rupture;severe acute pancreatitis
研究领域:
胃肠病学
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细胞生物学
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药理学
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高影响因子
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