CANCER SCIENCE
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2026
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IF 4.9
Jing Yang,Puyuan Chen,Yawen Zheng,Feiyue Shi,Min Wang,Luwei Xu,Xiaowei Wei,Xiumei Wang
Radioresistance in prostate cancer demands innovative sensitization strategies. We identified the glucocorticoid receptor nuclear receptor subfamily 3 group C member 1 (NR3C1) as a key negative regulator of radiosensitivity linked to poor prognosis. NR3C1 transcriptionally upregulates the lipid-metabolizing enzyme, acyl-CoA synthetase long-chain family member 4 (ACSL4), thereby enhancing cell proliferation, migration, and radioresistance. High ACSL4 expression sensitizes cells to ferroptosis inducers that amplify lipid peroxidation and restore radiosensitivity. Using the clinically applicable ferroptosis inducer, dihydroartemisinin (DHA), we found that DHA synergizes with ACSL4 to trigger ferroptosis, sensitizing radioresistant cells and xenografts to radiation. This effect was characterized by elevated lipid peroxidation and was reversed by the ferroptosis inhibitor deferoxamine. Collectively, our study revealed that the NR3C1-ACSL4 axis regulates lipid peroxidation and promotes radioresistance. Targeting this axis with DHA and using ACSL4 as a biomarker represents a promising preclinical strategy to overcome radioresistance in prostate cancer, pending further clinical validation.
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高影响因子
FOOD CHEMISTRY
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2026
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IF 10.4
Bo Zheng,Hui Wen,Xingwei Xiang,Bin Zheng,Tianjie Li
UFA molecular geometry directs hierarchical assembly of starch-lipid systems. • US-DHPM induces UFA-templated starch reassembly from helices to aggregates. • C18 UFAs promote ordered lamellar barriers and enhanced digestion resistance. • Long-chain PUFAs generate strain-induced heterogeneity and rapid digestion. • Digestive resistance is governed by barrier continuity rather than CI alone. The influence of unsaturated fatty acid molecular geometry on the assembly and digestive properties of starch-lipid complexes remains unclear. Here, five UFAs with distinct chain lengths and configurations were incorporated into gelatinized wheat starch via ultrasound-assisted dynamic high-pressure microfluidization to construct hierarchical complexes. Multiscale analyses showed that UFA geometry governed amylose helix inclusion, V-type crystallinity, and lamellar packing. Monounsaturated UFAs promoted compact ordered assemblies, whereas highly unsaturated UFAs generated looser interfacial structures. These differences were reflected in digestion behavior, with oleic-acid-based complexes exhibiting enhanced digestion resistance and delayed lipid release, while certain highly unsaturated systems such as DHA showed accelerated starch hydrolysis and fatty acid liberation. Notably the linoleic acid-based complex exhibited the highest resistant starch content of 20.77% and the slowest fatty acid release with 29.70% of fatty acids still retained after 120 min of digestion. Correlation analysis and molecular dynamics simulations further indicated that digestive resistance depends on the continuity of hierarchical packing rather than complexation efficiency alone. These findings clarify geometry-dependent structure-digestion relationships in starch-lipid complexes and support structure-guided design of systems with tunable digestive properties. Download: Download high-res image (203KB) Download: Download full-size image
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Wang Weilin,Hu Qiaoying,Wu Chunyan,Ding Jiayue,Zhu Chuanxiu,Wen Jiayao,Li Yingchao,Yang Menghan,Wang Yujie,Sun Deqing,Zhai Guangxi,Zhang Yanan
Ferroptosis and sonodynamic therapy (SDT) have both been recognized as powerful weapons in cancer treatment, especially in non-small-cell lung carcinoma (NSCLC) recently. However, the lack of effective sono-sensitizer and ferroptosis regulator limited their usage. In order to overcome the limitation, a novel nanoplatform of DTX-CS/ART/PFCA@RGD (cRCAPD) was fabricated based on SDT and ferroptosis. Nanoparticles, under the action of c(RGDfk) cyclic peptides and their skeleton chondroitin sulfate (CS), could specifically target αvβ3 and CD44 receptors, respectively, thereby targeting tumor sites. Meanwhile, the peroxy-bridge structure of ART disrupted the intracellular iron homeostasis while generating highly toxic reactive oxygen species (ROS) under the SDT. Docetaxel (DTX) in nanoparticles led to the excellent apoptosis of A549 cells. Oxygen carried by PFCA alleviated the tumor hypoxic microenvironment, downregulated HIF-1α, and provided substrates for SDT. Further, the nanoparticles showed a strong immunogenic cell death (ICD) effect, modulating the number of T cells and dendritic cells in tumor-bearing mice. In summary, the proposed therapeutic strategy based on SDT and ferroptosis holds promising potential for synergistic treatment of lung cancer in future clinical applications. Graphical The alternative text for this image may have been generated using AI.
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MOLECULAR IMMUNOLOGY
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2026
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IF 3.7
Suhong Ye,Ling Bao,Qiaolu Xu,Zihan Ding,Fei Wu,Xia Yuan,Yang Zhou,Nashwa Amin,Javaria Sundus,Marong Fang
Dihydroartemisinin (DHA) dose-dependently ameliorates ischemic brain injury and promotes neurological recovery in mice after ischemic stroke. • DHA inhibits ferroptosis in ischemic brain tissue via regulating iron homeostasis, lipid peroxidation and core ferroptosis-related proteins. • Astrocytic TAK1-CREB1 signaling pathway is identified as the key molecular target mediating the neuroprotective effects of DHA. • This study provides a promising drug repurposing candidate and novel therapeutic target for the clinical treatment of ischemic stroke. Background Ischemic stroke accounts for 87% of all stroke cases, and remains a leading cause of mortality and disability worldwide. Current reperfusion therapies are limited by narrow therapeutic windows, and cerebral ischemia-reperfusion injury (CIRI) remains a major clinical challenge. Ferroptosis, an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation, has been identified as a key pathological driver of CIRI. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has shown neuroprotective effects in ischemic stroke, but its underlying mechanism, especially the regulatory effect on ferroptosis via the TAK1-CREB1 signaling axis, remains unclear. Objective To investigate the neuroprotective effect of DHA in ischemic stroke and its molecular mechanism related to the TAK1-CREB1 signaling pathway and ferroptosis regulation. Methods Wild-type (WT) C57BL/6 J mice and astrocyte-specific CREB1 conditional knockout (CREB1 CKO) mice were used to establish a photothrombotic stroke (PTs) model. Neurological function was evaluated by modified neurological severity score (mNSS), Bederson score, Garcia scale and hanging test. Cerebral infarct volume was measured by TTC staining. Cerebral blood flow (CBF) was detected by laser speckle contrast imaging. Histopathological changes were observed by HE and Nissl staining. Mitochondrial ultrastructure was examined by transmission electron microscopy (TEM). The levels of malondialdehyde (MDA), glutathione (GSH), NADPH/NADP + ratio, ferrous iron (Fe 2+ ) and total iron in brain tissue were detected by biochemical kits. The expression of ferroptosis-related proteins and CREB1 was detected by Western blot and immunofluorescence staining. Results DHA treatment dose-dependently improved neurological function, reduced infarct volume, restored CBF, and ameliorated histopathological damage in PTs mice. TEM revealed that DHA reversed ferroptosis-typical mitochondrial changes in ischemic brain tissue. Biochemically, DHA decreased MDA, Fe²⁺, and total iron, while increasing GSH and NADPH/NADP⁺ ratio. Mechanistically, DHA dose-dependently upregulated GPX4, xCT, and FTH1, and downregulated ACSL4. Notably, astrocyte-specific CREB1 knockout nearly completely abolished DHA's neuroprotective and anti-ferroptosis effects. Conclusion DHA promotes neurological rehabilitation after ischemic stroke by targeting the astrocytic TAK1-CREB1 signaling pathway to inhibit ferroptosis. This study provides a novel theoretical basis and promising candidate drug for the clinical treatment of ischemic stroke.
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Advanced Science
·
2026
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IF 14.1
Chunyu Liu,Shun Wu,Chuang Wang,Zirui Zhou,Tianwei Cai,Wen Tao,Shidong Zuo,Chi Zhang,Yuhao Dong,Yi Feng,Qingbo Huang,Baojun Wang,Xin Ma,Haoli Ma,Xu Zhang,Yan Huang
Cellular senescence is a stable cell cycle arrest program with important therapeutic implications in cancer, yet how metabolic perturbations are translated into redox-dependent senescence remains incompletely understood. Here, we identify triosephosphate isomerase 1 (TPI1) as a critical regulator of senescence in clear cell renal cell carcinoma (ccRCC) through a customized CRISPR-Cas9 metabolic screen. TPI1 depletion induces a robust senescence phenotype characterized by mitochondrial redox imbalance, DNA damage, and stable growth arrest. Mechanistically, loss of TPI1 leads to accumulation of dihydroxyacetone phosphate (DHAP), which engages a SARM1-dependent signaling pathway, resulting in increased cyclic ADP-ribose (cADPR) production and intracellular Ca 2+ release. This cADPR-Ca 2+ axis drives mitochondrial ROS (mtROS) generation, thereby promoting DNA damage and activation of the p53-p21 pathway to enforce senescence. Pharmacological or genetic attenuation of calcium signaling, or mitochondrial ROS partially rescues these phenotypes, indicating that calcium-dependent redox stress is required for senescence induction. Importantly, this metabolic–redox signaling cascade is conserved across multiple cancer types. Collectively, our findings define a previously unrecognized TPI1–SARM1–cADPR–Ca 2+ axis that links glycolytic metabolite accumulation to mitochondrial redox stress and cellular senescence, highlighting a metabolite-driven redox vulnerability that may be therapeutically exploitable in cancer.
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International Journal of Nanomedicine
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2026
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IF 6.5
Dezhao Chen,Xiaohan Zheng,Qiao Gao,Bing Chen,Yang Sun
Purpose: Natural ferritin Fn) is a cage-like protein with a central cavity, making it a promising vehicle for drug delivery. However, its non-specific accumulation in iron-metabolizing organs impairs targeting precision and therapeutic efficacy. To overcome this challenge, we aimed to develop a novel biomimetic nanoplatform based on manganese-mineralized ferritin loaded with dihydroartemisinin (DHA@MFn) for precise ovarian cancer treatment, enabling controlled drug release and amplified therapeutic effects within the tumor microenvironment.Methods: We constructed a manganese-mineralized ferritin nanocage encapsulating DHA, resulting in DHA@MFn with favorable physicochemical properties, including a particle size of 12.2 nm and a zeta potential of − 13.54 mV. The stability, stimuli-responsiveness, and in vitro release behavior of DHA@MFn were evaluated under weakly acidic conditions. We assessed its ability to catalyze Fenton-like reactions releasing Mn2+, induce ferroptosis via lipid peroxidation and GSH depletion, and enable controlled drug release. In vivo biodistribution, tumor accumulation, and therapeutic efficacy were investigated using SKOV3 tumor-bearing mice, alone and in combination with irradiation.Results: DHA@MFn remained stable and demonstrated excellent responsiveness to the tumor microenvironment, releasing Mn2+ ions that catalyzed Fenton-like reactions for hydroxyl radical production. The nanoplatform facilitated targeted tumor accumulation and retention, significantly reducing off-target organ distribution, particularly in the liver. The release of DHA induced ferroptosis through lipid peroxidation and GSH depletion, enhancing oxidative stress. Combined with irradiation, DHA@MFn achieved superior tumor ablation through synergistic ferroptosis, photothermal effects, and minimal systemic toxicity compared to free DHA, MFn alone, or their combinations with irradiation.Conclusion: This multifunctional biomimetic nanoplatform presents a promising strategy for precise, multimodal ovarian cancer therapy. By integrating controlled drug delivery, catalytic Fenton-like reactions, and synergistic radiotherapy, DHA@MFn demonstrates significant potential for clinical translation in targeted cancer treatment.
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Nanomedicine-Nanotechnology Biology and Medicine
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2026
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IF 4.3
Wen Zhao,Jun Wang,Xiao-yue Du,Meng-ke Xie,Xiu-hua Zhao
A dihydroartemisinin (DHA)–stachyose conjugate (sDHA) was synthesized via succinate ester linkage to enhance solubility and anti-cerebral malaria efficacy. Structural characterization (FT-IR, 1 H NMR) confirmed a 1:1 M ratio. sDHA exhibited 55, 86, and 66 fold higher saturated solubility in water, simulated gastric fluid, and intestinal fluid (4.68 ± 0.36, 13.74 ± 1.07, and 10.62 ± 0.78 mg/mL) than free DHA, with a critical micelle concentration of 1.91 ± 0.32 mg/mL. In rats, oral sDHA achieved a 3.71-fold higher AUC 0-12h (14.56 ± 1.23 vs. 3.93 ± 0.41 μg·h/mL) and 2.75-fold longer absorption half-life ( t 1/2α : 3.37 ± 0.28 vs. 1.22 ± 0.15 h) versus DHA. In Plasmodium-infected mice, high-dose sDHA reduced parasitemia by 60% versus controls, lowered mortality by 33%–40%, extended survival by 26%–50%, and alleviated neurobehavioral deficits. This excipient-free oligosaccharide conjugate offers a translatable strategy for improving BCS IV antimalarial drugs.
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CHEMICAL ENGINEERING JOURNAL
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2023
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IF 15.1
Jing Yan,Kaicheng Zhang,Faguang Ma,Hang Cui,Yilin Wu
Membrane-based separations can improve energy efficiency and reduce the environmental impact associated with conventional methods. However, conventional adsorbents encapsulate most of their functional sites in their dense structures, leading to issues of low selectivity and adsorption capacity. To overcome the above problems, the scalable basswood-based PDA/GO-embedded self-assembly membranes were prepared based a multilayer artemisinin (Ars)-imprinted nanocage (MA/SB-P/G-ESMs) for highly selective adsorption and transport to Ars. The double-layer imprinting strategy of graphene oxide based on polydopamine and κ-carrageenan using three-dimensional mesoporous basswood as the support membrane improved the effective imprinting platform. The final MA/SB-P/G-ESMs were prepared by a heat-initiated radical polymerization, acrylamide was used as a functional monomer to conveniently and efficiently form specific recognition sites on the membrane. Notably, the outcomes demonstrated that, despite interference with other rivals, MA/SB-P/G-ESMs displayed perfect rebinding selectivity ( λ = 2.67, 2.89, 2.35) and perm-selectivity ( β = 8.16, 5.43, 6.51) for Ars. The high regeneration rate (after 10 cycles, greater than93%) demonstrated the MA/SB-P/G-ESMs' practical application potential. The selective separation of Ars using the MA/SB-P/G-ESM preparation method showed substantial promise in this work.
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Biomaterials Science
·
2023
·Vol. 11
·期 9
·3321-3334
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IF 6.6
Yifei Zheng,Chao Qin,Fei Li,Jingxin Qi,Xinyu Chu,Hao Li,Ting Shi,Zhen Yan,Lei Yang,Xiaofei Xin,Lisha Liu,Xiaopeng Han,Lifang Yin
Ferroptosis has been proposed as one form of iron-dependent cell death, overgeneration of high-toxicity hydroxyl radicals (˙OH) tumor sites via Fenton reactions induced cell membrane damage. However, the insufficient intracellular concentrations of both iron and H2O2 limited the anticancer performance of ferroptosis. In this study, ROS-sensitive prodrug nanoassemblies composed of a PEG2000-ferrous compound and a single thioether bond bridged dihydroartemisinin-paclitaxel prodrug were constructed, which fully tapped ex/endogenous iron, ferroptosis inducers, and chemotherapeutic agents. Following cellular uptake, the intracellular oxidizing environment accelerated the self-destruction of nanoassemblies and triggered drug release. In addition to the chemotherapeutic effect, the activated dihydroartemisinin was capable of acting as a toxic ˙OH amplifier via the reinforced Fenton reaction, simultaneously depleting intracellular GSH, as well as inducing glutathione peroxidase 4 inactivation, further enhancing ferroptosis-dependent cancer cell proliferation inhibition. Meanwhile, the ROS generation-inductive and cell cycle arrest effect from the paclitaxel augmented synergetic ferroptotic-chemotherapy of cancer. Thus, the prodrug integrating dihydroartemisinin with paclitaxel via a single thioether bond represents a potent nanoplatform to exert amplified ferroptotic-chemotherapy for improved anticancer efficacy.
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Frontiers in Molecular Biosciences
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2023
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IF 5
Shi Hanqiang,Xiong Lie,Yan Guang,Du Shuqin,Liu Jie,Shi Yanbo
The clinical therapeutics of cervical cancer is limited due to the drug resistance and metastasis of tumor. As a novel target for antitumor therapy, ferroptosis is deemed to be more susceptible for those cancer cells with resistance to apoptosis and chemotherapy. Dihydroartemisinin (DHA), the primary active metabolites of artemisinin and its derivatives, has exhibited a variety of anticancer properties with low toxicity. However, the role of DHA and ferroptosis in cervical cancer remained unclear. Here, we showed that DHA could time-dependently and dose-dependently inhibit the proliferation of cervical cancer cells, which could be alleviated by the inhibitors of ferroptosis rather than apoptosis. Further investigation confirmed that DHA treatment initiated ferroptosis, as evidenced by the accumulation of reactive oxygen species (ROS), malondialdehyde (MDA) and liquid peroxidation (LPO) levels and simultaneously depletion of glutathione peroxidase 4 (GPX4) and glutathione (GSH). Moreover, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy was also induced by DHA leading to subsequent increases of intracellular labile iron pool (LIP), exacerbated the Fenton reaction resulting in excessive ROS production, and enhanced cervical cancer ferroptosis. Among them, we unexpectedly found that heme oxygenase-1 (HO-1) played an antioxidant role in DHA-induced cell death. In addition, the results of synergy analysis showed that the combination of DHA and doxorubicin (DOX) emerged a highly synergistic lethal effect for cervical cancer cells, which was related also to ferroptosis. Overall, our data revealed the molecular mechanisms that DHA triggered ferritinophagy-dependent ferroptosis and sensitized to DOX in cervical cancer, which may provide novel avenues for future therapy development.
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ACS Applied Bio Materials
·
2023
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IF 4.7
Jingsong Lu,Jing Yu,Wensheng Xie,Zhenhu Guo,Xiaohan Gao,Ying Li,Ziqing Zhang,Zeping Jin,Abdul Fahad,Shenglei Che,Lingyun Zhao,Yen Wei
Since the nonspecificity and nonselectivity of traditional treatment models lead to the difficulty of cancer treatment, nanobased strategies are needed to fill in the gaps of current approaches. Herein, a tumor microenvironment (TME)-responsive chemo-photothermal treatment model was developed based on dihydroartemisinin (DHA)-loaded conjugated polymers (DHA@PLGA-PANI). The synthesized DHA@PLGA-PANI exhibited enhanced photothermal properties under mild-acidic conditions and thus triggered local heat at the tumor site. Meanwhile, these iron-doped conjugated polymers of PLGA-PANI were used as the source of Fe, and benefiting from the Fe-dependent cytotoxicity of DHA, the burst of free radicals could be generated in tumors. Therefore, the combination of TME-responsive chemo-photothermal therapy could achieve effective tumor efficacy.
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Biomaterials Science
·
2023
·Vol. 11
·期 7
·2478-2485
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IF 6.6
Yawei Li,Wei Zhang,Naiyuan Shi,Wenqing Li,Junxia Bi,Xianmin Feng,Nianqiu Shi,Wenhe Zhu,Zhigang Xie
Dihydroartemisinin (DHA), a plant-derived natural product, has recently been proven to be an effective therapeutic agent for cancer treatment. Nevertheless, the poor water solubility and low bioavailability of DHA seriously impede its clinical applications. Herein, a simple and green strategy based on the self-assembly of DHA was developed to synthesize carrier-free nanoparticles (NPs). The resulting nanodrug (DHA NPs) was formed by the self-assembly of DHA molecules via hydrogen bonding and hydrophobic interactions. The DHA NPs exhibited a near-spherical morphology with narrow size distribution, favorable drug encapsulation efficiency (>92%), excellent stability, and on-demand drug release behavior. Furthermore, the in vitro and in vivo experiments revealed that the DHA NPs exhibited significantly higher therapeutic efficacy than the DHA equivalent. In addition, we further explored the potential molecular mechanism of the DHA NPs by utilizing RNA-seq technology and western blotting analysis, which demonstrated that the p53 signaling pathway plays a crucial part in the process of inhibiting tumor cell growth and inducing apoptosis. This work not only reveals the rationale for developing pure nanodrugs via the self-assembly of natural small molecules for oncotherapy but also the investigation of the antitumor mechanism and provides novel theoretical support for the clinical usage of DHA.
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