JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2025
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IF 9.7
Bowen Song,Ziye Zhao,Zhanhong Qiao,Ji Li,Dawei Chen,Ming Zhao,Haiyang Hu
Despite significant advancements in tumor immunotherapy, challenges including insufficient immunogenicity and immunosuppressive microenvironment continue to hinder therapeutic effect. The immunogenic cell death (ICD) enhances the tumor immune microenvironment and potentiate immunotherapy response. Certain chemotherapeutic agents can induce ICD; however, their limited immunogenicity, poor tumor-site targeting, and low tumor permeability restrict their efficacy. Herein, bacteria-driven liposomes were designed. Liposomes co-loaded with mitoxantrone (MTO) and iron ions (Fe 3+ ) were engineered to leverage the hypoxia-responsive properties of Escherichia coli Nissle 1917 (EcN) for precise tumor-site targeting. In the acidic tumor environment, mitoxantrone/ferric ions liposomes (LFM) released Fe 3+ and MTO. Intracellular Fe 3+ is reduced to Fe 2+ , catalyzing the Fenton reaction to generate reactive oxygen species (ROS) and induce ferroptosis. Concurrently, mitoxantrone (MTO) exerts direct cytotoxic effects on tumor cells. The synergistic interplay of these mechanisms significantly enhances the immunogenicity of tumor cells, triggering ICD and subsequently activating systemic antitumor immune responses. The drug delivery system constructed in this study integrated chemotherapy, ferroptosis, and immune activation, providing an innovative and effective strategy for tumor therapy. This approach paves the way for advanced combination therapies in cancer treatment.
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Journal of Advanced Research
·
2025
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IF 13
Minyi Zhang,Qi Wang,Chen Li,Mengyao Chen,Chunhui Wang,Zikang Wang,Tao Xia,Chengqing Yi,Shuo Shi
Introduction Ion interference therapy has emerged as a promising new treatment for Osteosarcoma (OS). However, its efficacy is significantly restricted by inadequate hydrogen peroxide (H 2 O 2 ) under the complex tumor microenvironment (TME). Objectives This study aimed to supply sufficient H 2 O 2 to enhance tumor therapy efficacy and address the limitations associated with ion interference. Methods A hollow manganese dioxide (HMnO 2 ) nanoplatform loaded with calcium peroxide (CaO 2 ) (denoted as HMnO 2 @CaO 2 ) was evaluated for biosafety through hemolysis tests. The functionality of HMnO 2 @CaO 2 was further validated by quantitative real-time polymerase chain reaction (qRT-PCR) and cytometric analysis. Results Excessive Ca 2+ accumulation induces endoplasmic reticulum (ER) stress, enhances oxidative stress, and causes mitochondrial damage. Notably, Mn 2+ facilitates treatment monitoring through magnetic resonance imaging (MRI). Additionally, Mn 2+ -induced ferroptosis triggers an immune response that promotes the polarization of tumor-associated macrophages (TAMs), transforming the pro-tumoral M2 phenotype into the tumoricidal M1 phenotype, thereby enhancing the efficacy of immunotherapy. Conclusion In conclusion, HMnO 2 @CaO 2 nanoplatform enhances tumor therapy efficacy by overcoming ferroptosis limitations, inducing Ca 2+ overload, and boosting anti-tumor immunity. This strategy offers a promising approach to ion interference in the clinical translation of nanomedicines. Furthermore, it marks a significant advancement in osteosarcoma (OS) treatment and underscores the transformative potential of nanotechnology in medicine.
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RENAL FAILURE
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2026
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IF 3.8
Yongli Yang,Zhiying Xiao,Liangjin Liu,Tingting Hu,Yi Liu,Duan Wang
Acute kidney injury (AKI) is a frequent complication of sepsis. It has been reported that curcumin can alleviate sepsis-associated AKI (SA-AKI). This study aims to elucidate the regulatory effects and mechanisms of curcumin on ferroptosis in the context of SA-AKI. In this study, septic mice and lipopolysaccharide-stimulated HK-2 cells were employed to simulate the pathological conditions of SA-AKI. The status of renal injury and ferroptosis-related indicators was determined to assess the regulatory effect of curcumin on ferroptosis in SA-AKI. Furthermore, the expression of α7 nicotinic acetylcholine receptor (α7nAChR) was intervened to investigate the specific protective mechanism of curcumin in SA-AKI. Finally, the nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor ML385 was incorporated to further elucidate the potential pathway through which α7nAChR regulates ferroptosis. The results demonstrated that curcumin exerted a significant protective effect on SA-AKI cells and animal models, markedly reducing cellular damage and renal injury in mice, attenuating the inflammatory response, and effectively inhibiting ferroptosis in renal cells and tissues. Furthermore, curcumin treatment upregulated the expression of α7nAChR in both SA-AKI cells and animal models. Nevertheless, the inhibition of α7nAChR expression partially counteracted the ameliorative effects of curcumin on injury and ferroptosis in SA-AKI cells and animal models. The overexpression of α7nAChR attenuated LPS-induced ferroptosis in HK-2 cells, whereas ML385 reversed the inhibitory impact of α7nAChR upregulation on cellular ferroptosis. In conclusion, these findings indicate that curcumin suppresses ferroptosis by upregulating α7nAChR to activate the antioxidant capacity of NRF2, thereby providing a protective effect against SA-AKI.
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Frontiers in Pharmacology
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2026
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IF 5.4
Binwei Jin,Yang Zhang,Jiangbo Lin,Yu Zhu,Mengqi Yang,Yutao Zhang,Yanping Yin,Zhiming Zhang,Minjun Yang,Jianjun Jiang,Yafei Mi
Background Myocardial ischemia-reperfusion injury (MIRI) remains a therapeutic challenge with limited treatment options. Ferroptosis, characterized by lipid peroxidation, contributes significantly to MIRI pathogenesis. This study investigates whether dihydromyricetin (DHM), a bioactive flavonoid from Ampelopsis grossedentata , alleviates MIRI by inhibiting ferroptosis, and explores its cardioprotective mechanisms. Methods A mouse myocardial I/R model was established in vivo by ligating the left anterior descending coronary artery for 30 min, followed by reperfusion for one or 7 days. Mice were pretreated with DHM (125 or 250 mg/kg, gavage) for 4 weeks, or with Fer-1 (10 mg/kg) for 1 week. In vitro , an OGD/R model was constructed using H9c2 cells, which were then treated with DHM (0–200 μM) or Fer-1 (10 μM). Potential targets were screened via network pharmacology. Target interaction was validated through biotin-pull-down, molecular docking, CETSA, and DARTS assays. Functional validation was performed using PPARα-knockdown and rescue cell lines. Results GSEA indicated significant activation of the ferroptosis pathway in MIRI, and cellular experiments confirmed that OGD/R induced a typical ferroptosis phenotype. DHM dose-dependently reversed OGD/R-induced ferroptosis-related alterations and ameliorated mitochondrial ultrastructural damage. In vivo , DHM pretreatment significantly reduced serum CK-MB levels, myocardial infarct size, and histopathological injury in I/R mice, while reversing cardiac ferroptosis marker changes. Mechanistically, network pharmacology identified seven overlapping targets, among which DHM specifically reversed the downregulation of PPARα. Biochemical assays and molecular docking confirmed that DHM directly binds to and stabilizes PPARα via the E286 site. Knockdown of PPARα markedly attenuated the anti-ferroptotic and cardioprotective effects of DHM, whereas PPARα rescue partially restored its function. Conclusion This study demonstrates for the first time that DHM alleviates ischemia-reperfusion injury by directly targeting the E286 site of PPARα, upregulating its levels, and thereby suppressing cardiomyocyte ferroptosis. This finding reveals a novel mechanism underlying the cardioprotective effect of DHM and provides a new theoretical basis for targeting the PPARα-ferroptosis axis in MIRI intervention.
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Advanced Healthcare Materials
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2026
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IF 11
Jiahui Wang,Wanxin Hou,Xiuxiu Qiu,Yu Zhang,Li Tao,Yukun Chen,Beibei Hong,Lei Zhou,Hegen Li,Zhanxia Zhang
Lung cancer metastasis is the primary cause of patient mortality, underscoring an urgent need for highly effective and low-toxicity therapies. Ursolic acid (UA), a natural triterpenoid, possesses potent antitumor activity, yet its clinical translation has been hindered by poor water solubility, low bioavailability, and nonspecific distribution. To overcome these limitations, we developed a UA-loaded iron-based metal–organic framework (MOF) nanomedicine, termed Ursolic Acid-loaded Iron-MOF (UA@MOF). Harnessing the high surface area and tunable porosity of MOFs, this system enables efficient UA encapsulation and promotes tumor-targeted delivery through the enhanced permeability and retention (EPR) effect. Once internalized, UA suppresses the Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling pathway, while iron ions released from the MOF induce ferroptosis in tumor cells via Fenton reactions. Together, these dual mechanisms act synergistically to inhibit tumor growth and metastasis. This work presents a novel strategy to improve the delivery and efficacy of natural antitumor agents, offering promising potential for the treatment of metastatic lung cancer.
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Journal of Advanced Research
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2026
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IF 17.1
Weichen Dong,Wenxin Zhang,Li Huang,Lulu Xiao,Yuanfei Luo,Linying Yuan,Yike Jiang,Anyu Liao,Hongting Zhao,Zhihui Liu,Jia Wang,Ying Zhao,Yulong Cai,Mengna Peng,Dong Yang,Yi Xie,Kuanyu Li,Wusheng Zhu
Introduction Cardiolipins (CLs) are mitochondria-specific phospholipids critically involved in neurological disorders. However, their role in cerebral ischemia/reperfusion (I/R) injury remains largely underexplored. Objectives This study aimed to characterize CL alterations following cerebral I/R injury, identify potential mechanisms underlying CL loss, and investigate the pathophysiological effects of these changes. Methods Ischemic stroke was modeled by using middle cerebral occlusion/reperfusion (MCAO/R) in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro . CL alterations following cerebral I/R injury were evaluated through lipidomic analysis and fluorescent staining. The role of extracellular vesicles (EVs) in CL release was investigated. The effects of CL-targeting peptide SS-31 on CL release and homeostasis were assessed, and underlying mechanisms were explored by analyzing neuronal autophagy and ferroptosis. Plasma CL levels in stroke patients were also measured to elucidate clinical relevance. Results Significant CL depletion and acyl chain remodeling were observed in peri -infarct brain tissues. EV-mediated release was identified as one of the mechanisms of CL loss, and inhibiting EV release restored neuronal CL levels. SS-31 inhibits CL release, preserves CL content, and subsequently restores CL homeostasis. Restoring CL homeostasis attenuated cerebral I/R injury by suppressing neuronal ferroptosis. Mechanistically, SS-31 downregulated autophagy-associated genes, with ATG5 identified as the crucial target. Activating autophagy or overexpressing ATG5 reversed the protective effects of SS-31. Clinically, plasma CL levels in patients undergoing endovascular treatment correlated with 90-day functional outcomes. Conclusion Our findings establish CL preservation as a novel neuroprotective strategy, in which SS-31 mitigates I/R injury by restoring CL homeostasis and ameliorating ATG5-mediated autophagy-dependent neuronal ferroptosis, offering a novel therapeutic avenue for stroke.
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Deng Yu,Tao Yongjian,Qing Yali,Wang Jianwei,Jie Chuanhong
Ethnopharmacological relevance Diabetic retinopathy (DR) is a severe microvascular complication of diabetes that is closely associated with hyperglycemia-induced mitochondrial dysfunction. Lishui Xiaozhong granules (LSXZ) are an empirical traditional Chinese medicine used to treat DR. However, its precise molecular targets and underlying mechanisms remain unclear. Aim of the study This study investigated whether LSXZ protects retinal cells under hyperglycemic conditions by regulating PINK1/Parkin-mediated mitophagy. Materials and methods Human Müller cells were exposed to high glucose (HG; 50 mM) to establish an in vitro model and treated with LSXZ-containing serum and the mitophagy inhibitor cyclosporin A (CsA). Genetic knockdown via siRNA was performed to validate the necessity of the PINK1/Parkin pathway. A zebrafish DR model was induced using an HG, high-fat diet, and treated with different LSXZ concentrations. Cell viability, mitophagy, apoptosis, ferroptosis, mitochondrial function, and ultrastructural changes were assessed using CCK-8 assays, western blotting, qPCR, immunofluorescence, and transmission electron microscopy. Retinal histopathology, vascular diameter, inflammatory cell activation, oxidative stress, and gene expression profiles in zebrafish were assessed using hematoxylin–eosin staining, fluorescence microscopy, and transcriptomic sequencing. Results LSXZ treatment reversed pathological changes by restoring PINK1/Parkin signaling, elevating LC3-II/LC3-I ratio, enhancing mitochondrial function, and suppressing apoptosis and ferroptosis—effects partially attenuated by CsA. Mitophagosomes increased after LSXZ treatment. Crucially, specific knockdown of PINK1 or Parkin significantly abolished LSXZ-induced cytoprotection, reversing the regulation of apoptotic/ferroptotic markers and mitochondrial recovery, thereby confirming the pivotal necessity of this pathway. In zebrafish, LSXZ alleviated hyperglycemia-induced retinal inner nuclear layer thinning, vascular dilation, excessive macrophage/astrocyte activation, and oxidative stress. These protective effects were mediated through upregulation of the TOMM40/TOMM20–PINK1/Parkin–MFN2 axis.
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Antioxidants
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2026
·Vol. 15
·期 6
·722
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IF 8.2
Quan Zhu,Yangyang Zhang,Xinyi Zhu,Huijuan Zhang,Chuyu Xiao,Yingying Yang,Ting Huang,Jun Lu,Chang Liu,Chunjing Chen,Yueyuan Zhou,Tao Liu,Biyuan Liu,Fangguo Lu
Ferroptosis and cuproptosis are promising anti-tumor treatment strategies. Elesclomol (ES) is a kind of common cuproptosis inducer, and cisplatin (DDP) is a commonly used drug in liver cancer chemotherapy, which can induce cells to undergo ferroptosis. Both of these cell death processes require inducing cells to generate oxidative stress. Therefore, elesclomol and cisplatin may have a synergistic effect in anti-tumor treatment. Here, we designed an active oxygen-responsive nano-delivery system and conducted in vitro and in vivo to study the synergistic anti-liver cancer effect of elesclomol and cisplatin. Our data showed that the elesclomol nanoparticles can effectively inhibit the growth of liver cancer cells and showed extremely low organ toxicity. Elesclomol exhibited a synergistic effect with cisplatin in vitro, but the combined treatment of the two did not outperform single drug treatment in vivo. The reason might be that the nuclear factor erythroid 2-related factor 2 (Nrf2) protein in liver cancer cells is feedback-expressed, inhibiting the oxidative stress effects induced by elesclomol and cisplatin. Therefore, this study provides reference data for exploring the mechanism of elesclomol’s synergistic anti-liver cancer treatment with cisplatin and offers a feasible strategy for future precise liver cancer treatment and improving chemotherapy efficacy.
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Communications Biology
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2026
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IF 5.8
Zhang Han,Gu Xinsheng,Sun Yidan,Chen Pengcheng,Hu Qiangsheng,Li Hao
The roles of glutamic-oxaloacetic transaminase 2 (GOT2) in malate-aspartate shuttle (MAS), fatty acid binding/trafficking, and peroxisome proliferator-activated receptor (PPAR) delta axis have been documented. However, its function in ferroptosis remains unexplored. Here, we report that GOT2 promotes ferroptosis by disturbing mitochondrial redox homeostasis through inhibiting the synthesis of radical scavenger coenzyme Q10 (CoQ 10 ). Mechanism, by fueling MAS, GOT2 increases net influx of NADH into mitochondria and enhances aerobic respiration, increasing cellular ATP generation. The high ATP/ADP ratio inactivates adenosine 5′-monophosphate-activated protein kinase (AMPK) and PPARα, downregulating the transcription of core enzymes in CoQ 10 synthesis pathway (FDPS, PDSS1/2, COQ3/5/6). In lung adenocarcinoma (LUAD), high expression of GOT2 restrains tumor progression by activating ferroptosis and igniting antitumor immunity. Whereas, the activation of GOT2-mediated ferroptosis exacerbates lesion in atherosclerosis disease. Our study reveals that GOT2-AMPK-PPARα-CoQ 10 axis is a novel pro-ferroptosis pathway, and modulating GOT2-mediated ferroptosis suggests an intriguing method to treat LUAD and atherosclerosis. The alternative text for this image may have been generated using AI.
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JOURNAL OF MEDICINAL CHEMISTRY
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2026
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IF 7.3
Rui-Xue Liu,Dong-Mei Li,Ru-Yi Luo,Xue-Bin Bi,Yue Huang,Sha-Sha Luo,Ying-Shu Wu,Tong-Yan Ding,Jia-Xiu Xie,Chang-Chun Wen,Yan-Cheng Liu,Tim Storr,Hong Liang
A new nonsymmetric anthrahydrazone ligand (AAIH) was designed and synthesized, affording novel manganese(II) and cobalt(II) complexes, AAIH-Mn and AAIH-Co. Both complexes crystallized in the same centrosymmetric dinuclear coordination mode, however, AAIH-Mn exhibited much higher in vitro cytotoxicity (IC50 = 1.64 μM against MGC-803 cells) than AAIH-Co (IC50 = 10.05 μM) and AAIH (IC50 = 18.82 μM), signifying the importance of the Mn(II) center. Furthermore, AAIH-Mn exerted anticancer activity via multiple pathways: S-phase cell cycle arrest, cell apoptosis, autophagy and notably, the emerging process of ferroptosis. AAIH-Mn also effectively inhibited 56% of tumor growth in vivo on MGC-803 xenografts at 16 mg/kg, without causing obvious toxicity. Low toxicity was further supported by zebrafish models, along with its anti-inflammatory activity and low cardiotoxicity. As the first Mn(II) complex inducing ferroptosis, AAIH-Mn provides a valuable example of a low-toxicity metal center to generate highly cytotoxic nonplatinum anticancer complex.
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JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE
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2026
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IF 4.7
Hailong Feng,Hongtao Luo,Xiugeng Li,Yang Jiang,Baihui He
Ferroptosis is a novel anticancer therapeutic approach that effectively circumvents the apoptotic cell death mechanism. Nonetheless, enhancing the catalytic effectiveness of the Fe 2+ -mediated Fenton reaction and effectively inducing ferroptosis present significant challenges. In this study, motivated by the kinetics of hyperthermia-improved Fenton reactions, we initially developed Quercetin (QT)-Curcumin (CUR)-Iron (Fe)-coordinated nanochelates for photothermal-improved ferroptosis in anticancer therapy. We precisely adjusted the appropriate feeding rate of polyvinylpyrrolidone (PVP), QT, CUR, and Fe to develop unique nanofibrous QT-CUR-Fe chelates, referred to as QCFs. The differences in size and structure made QCFs more practical for colorectal cancer therapy than ultrasmall QT-Fe (QFs). Under NIR laser exposure, QCFs can continuously enhance the formation of depleted excessive GSH and toxic hydroxyl radicals (•OH), leading to increased lipid peroxidation (LPO) accumulation and subsequently activating the ferroptosis pathway in vitro. Furthermore, the incorporation of CUR may suppress prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) in conjunction with PTT-improved ferroptosis colorectal therapy to facilitate dendritic cell (DC) maturation, elicit immunogenic cell death (ICD), and enhance synergistic antitumor immunotherapy. Overall, this study proposed a way to integrate small-molecule immunomodulators into QFs nanocoordination to overcome its limitations, thereby fostering a novel design concept for colorectal cancer therapy.
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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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