INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2025
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IF 5.2
Bo Yi,Haiyang Zhou,Jing Chen,Lei Sun
The brief lifetime of reduced O 2 levels and oxygen species during ferroptosis in cancer cell lines undermines the ferroptosis efficacy. Enhancing the effectiveness of real-time created active oxygen species is crucial for pancreatic adenocarcinoma. The Evofosfamide (EFA) encapsulated polydopamine (PD)-iron (Fe) nanoparticles (Fe/PD-EFA) were modified with unsaturated liposomes (Lipo) to address the limitations of conventional ferroptosis therapy. The Lipo@Fe/PD-EFA can interact with H 2 O 2 to generate •OH, which subsequently targets Lipo, resulting in the formation of a phospholipid peroxide radical (LOO•) and a radical intermediate (L•) to mitigate the detrimental effects of the •OH. Liposomes facilitate oxygen consumption and augment lipid peroxidation, thereby exacerbating hypoxia at the site of pancreatic cancer. The EFA can be activated by reductase in cancer cell lines under a hypoxic milieu, which diminishes free radicals through the reductase enzyme and disrupts the adjacent biomacromolecules’ structure, thereby facilitating the synergistic therapy of chemotherapy and ferroptosis in Panc-1 cells. This study integrates improved ferroptosis with hypoxia-activated chemotherapy to generate an effective and targeted tumoricidal impact, perhaps offering a promising treatment for pancreatic adenocarcinoma (PDAC) in the future.
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ADVANCED FUNCTIONAL MATERIALS
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2025
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IF 19
Qin Li,Meng Zeng,Xiaoyan Pu,Qi Tang,Qian Yang,Liangke Zhang
In ulcerative colitis (UC), oxidative stress (OS) and iron overload disrupt immune homeostasis and intestinal barrier function, exacerbating inflammation through effects on macrophages and intestinal epithelial cells (IECs). Reversing macrophage-driven inflammation and restoring homeostasis of IECs are effective strategies for treating UC. In this study, a multifunctional nanozyme (PDA-Rh@Mel) is reported consisting of polydopamine nanoparticles (PDA) as the core, in situ-grown rhodium (Rh) aggregates, and loaded melittin (Mel). PDA-Rh@Mel efficiently aggregates at the site of inflammation through electrostatic interactions, exhibits cascading enzyme catalytic activity to reduce OS, and performs macrophage reprogramming. By chelating iron ions, scavenging reactive oxygen and nitrogen species, and protecting mitochondria, PDA-Rh@Mel maintains homeostasis of IECs, preventing further barrier damage and exacerbation of UC. Network pharmacological and histological evaluations show that PDA-Rh@Mel alleviated symptoms by inhibiting the IL-17 signaling pathway. These findings demonstrate that PDA-Rh@Mel can maintain redox balance, iron homeostasis, and immune equilibrium, representing a highly promising therapeutic strategy for UC.
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CANCER RESEARCH
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2025
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IF 16.6
Zhou Hai-Meng,Liu Yi,Shi Feng,Qiu Hao-Wen,Li Le,Shu Qi-Peng,Liu Yu-Ying,Wang Bai-Qi,Gao Meng,Du Run-Lei,Ke Shao-Bo,Zhang Xiao-Dong
Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, plays a crucial role in colorectal cancer (CRC) progression and therapeutic response. The NRF2 pathway is one of the critical axes in ferroptosis regulation, which governs oxidative stress resistance and iron homeostasis through its downstream targets, including HMOX1, SLC7A11, and others. However, HMOX1 and SLC7A11 exhibit contrasting roles in ferroptosis, with HMOX1 promoting ferroptosis via iron accumulation and lipid peroxidation, while SLC7A11 inhibits ferroptosis by enhancing antioxidant defenses. Here, we identified CLK2 as a key regulator of the delicate balance of the opposing effects of HMOX1 and SLC7A11. CLK2 stabilized KEAP1 to suppress NRF2 activity, resulting in the downregulation of HMOX1 and SLC7A11. Simultaneously, CLK2 downregulated p53, thereby relieving p53-mediated repression of SLC7A11. The dual regulation by CLK2 disrupted the balance between HMOX1 and SLC7A11, leading to excessive activation of HMOX1 in the absence of CLK2, ultimately sensitizing CRC cells to ferroptosis. Additionally, CLK2 promoted CRC proliferation and tumorigenesis in patient-derived organoids, cell lines, and mouse models. Furthermore, combining the ferroptosis inducer Erastin with Oxaliplatin significantly enhanced anti-tumor efficacy in CLK2-deficient xenograft models. Together, this study establishes CLK2 as a critical inhibitor of ferroptosis via the KEAP1/NRF2/HMOX1 and p53/SLC7A11 axes, supporting its potential as a therapeutic target for CRC.
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CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Zhiyi Hu,Danruo Luo,Yanjie Wang,Qi Wang,Renjie Ma,He Guo,Guodong Zhang,Qiuling Ma,Jian Zhou,Tiecheng Wang,Lingyan Zhu
The rapid spread of antibiotic-resistant bacteria (ARB) is a global health threat. Electrochemically active bacteria (EAB) driven by iron (oxyhydr)oxides can combat ARB by generating reactive oxygen species (ROS). However, the roles of extracellular ROS and intracellular ROS from ferroptosis in ARB inactivation remain unclear. This study developed a system combining Shewanella oneidensis MR-1 with single-atom iron catalysts (Fe-SAC/g-C 3 N 4 - S. oneidensis MR-1) to inactivate antibiotic-resistant Escherichia coli (AR E. coli ). This system exhibited superior electron transfer capacity, facilitating dissimilatory iron reduction and Fenton reactions. Compared to Fe-SAC/g-C 3 N 4 , the AR E. coli inactivation rate constants decreased by 55.50 %, 51.47 %, and 48.99 % for goethite, hematite, and ferrihydrite, respectively. Molecular docking revealed that hydrophobic interactions mediated extensive binding sites and reduced binding free energy between Fe-SAC/g-C₃N₄ and proteins, enhancing ROS generation. Extracellular ·OH was a major contributor to inactivation, while Fe 2+ entry triggered ferroptosis, accounting for 20 % of AR E. coli inactivation. Transcriptomic analysis revealed significant upregulation of genes associated with oxidative stress responses and iron transport, alongside attenuation of energy metabolism and cellular respiration. These findings highlighted the dual roles of endogenous ROS from ferroptosis and exogenous ROS from Fenton-like reactions in ARB resistance reduction.
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CELL DEATH AND DIFFERENTIATION
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2025
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IF 15.4
Fan Kexin,Zhou Shuting,Ren Yakun,Xiong Jingwen,Wang Hua,Fu Yaxin,Chen Yuhan,Wang Bobo,Fan Kun,Gao Min,Guo Tingli,Wei Xiaofeng,Jiao Lianying,Shi Jiejun,Ding Chenguang,Zhang Yilei
The tumor suppressor BRCA1-associated protein 1 (BAP1) encodes a nuclear deubiquitinase that specifically removes H2A monoubiquitination at Lys119 (H2Aub) and plays a crucial role in the epigenetic regulation of gene expression through cooperating with several transcriptional factors and chromatin-modifying enzymes. Our previous studies have confirmed that BAP1 represses SLC7A11-mediated cystine metabolism and promotes ferroptosis-dependent tumor suppression. However, how BAP1 regulates gene expression at the genome level and whether additional mechanisms are involved in the BAP1 regulation of ferroptosis remain unclear. Here, we integrate multi-omics analyses to explore the effects of BAP1-mediated H2Aub deubiquitination on the regulation of chromatin accessibility and gene transcription. Notably, we identified a novel target gene, ACSL4, which is positively regulated by BAP1 and contributes to BAP1-mediated ferroptosis. Importantly, genetic knockout or pharmacological inhibition of ACSL4 prevents the upregulation of lipid biosynthesis and ferroptotic cell death caused by BAP1. In addition, we demonstrated that BAP1-mediated regulation of gene expression and ferroptosis is dependent on ASXL family members instead of other BAP1-associated factors like FOXK1/2, HCFC1, and OGT. Together, our findings uncover a previously unappreciated epigenetic mechanism underlying the regulation of ACSL4 by H2A monoubiquitination, which connects ACSL4-mediated lipid metabolism to ferroptosis driven by BAP1, providing new insights into the understanding of metabolic regulation of BAP1-related diseases such as cancers.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2025
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IF 5.6
Jiashuai Yan,Di Wu,Biwen Zhu,Xiaoqi Guan,Xue Zhang,Yibing Guo,Yuhua Lu
As a highly aggressive solid tumor, pancreatic ductal adenocarcinoma (PDAC) is featured by a conspicuous tumor microenvironment (TME) with abundant extracellular matrix (ECM) deposition, such as collagen and hyaluronic acid (HA). Accompanying with the pathological process, the dense matrix caused stiffen microenvironment, which leads to poor chemotherapy. Therefore, understanding the potential mechanism of mechanical microenvironment on PDAC chemoresistance is of great significance. To this end, 3D printed methacrylated gelatin (GelMA) and hyaluronic acid methacryloyly (HAMA) hydrogel model was fabricated to resemble the mechanical microenvironment of PDAC. The results presented that the PDAC cell lines (MIA-PaCa2 and PANC-1) embedded in the hydrogel were distinctively less sensitive to gemcitabine compared to tissue culture plate (TCP) group. Interestingly, immunofluorescence staining and qRT-PCR assay demonstrated that the NRF2 level was elevated, which further upregulated the downstream effectors, such as SLC7A11 and GPX4. Meanwhile, the GSH concentration and GPX4 activity of hydrogel group were increased, while the lipid peroxidation level was reduced, which indicated that the matrix stiffness microenvironment mediated ferroptosis phenotype. Furthermore, RNA interference experiment elaborated that shNRF2 group showcased significantly enhanced sensitivity to gemcitabine, which demonstrated that the biomimetic microenvironment modulated chemoresistance through ferroptosis. All in all, the 3D printed model may serve as a new platform for illustrating the underlying mechanism of the TME induced chemoresistance, and also proposed a novel therapeutic strategy for PDAC through NRF2 inhibition, which effectively promotes ferroptosis to overcome chemoresistance.
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Liver Research
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2025
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IF 2.1
Qian Zeng,Yina Sun,Mengzhen Lei,Zihan Liu,Xijing Yan,Rong Li,Jun Zheng,Jiandong Zha,Lijun Zhang,Xiaoling Guan,Jia Yao
Background and aims Hepatic ischemia-reperfusion injury (HIRI) is a major contributor to liver dysfunction and failure, particularly in the context of liver transplantation. Its pathogenesis is primarily driven by ferroptosis, oxidative stress, and mitochondrial dysfunction. Given the interplay among these mechanisms through redox imbalance and disrupted energy metabolism, nicotinic acid (NA)—recognized for its antioxidative and metabolic regulatory properties—emerges as a promising therapeutic candidate. This study aims to investigate the protective effects of NA on HIRI and elucidate its underlying mechanisms. Methods An HIRI model in mice and a hypoxia/reoxygenation (H/R) model in primary hepatocytes were established to evaluate the effects of NA treatment on oxidative stress. NA was administered prior to model induction. N-acetylcysteine (NAC) was used as a comparator. Comprehensive assessments of ferroptosis, oxidative stress, mitophagy, and mitochondrial biogenesis markers were conducted using Western blotting, immunohistochemistry, immunofluorescence, and biochemical assays. Results NA pretreatment reduced serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase (LDH) levels, suppressed inflammation by decreasing neutrophil infiltration and macrophage activation, and mitigated oxidative stress by lowering reactive oxygen species (ROS) and malondialdehyde (MDA) levels. It enhanced antioxidant defenses, inhibited ferroptosis, and improved mitochondrial health through increased mitophagy, mitochondrial biogenesis, and mitochondrial permeability transition pore (mPTP) stabilization, leading to enhanced ATP production and mitochondrial function in HIRI. Conclusions NA improves mitochondrial function by promoting mitophagy and mitochondrial biogenesis, which reduces ferroptosis and oxidative stress, thereby alleviating HIRI.
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Bioengineering & Translational Medicine
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2025
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IF 5.7
Lulu Chen,Bicheng Chen,Xiang Su
An abdominal aortic aneurysm (AAA) is a life-threatening vascular condition characterized by the dilation of the abdominal aorta, with ferroptosis playing a significant role in its pathogenesis. This study investigates the therapeutic potential of engineering biomimetic nanovesicles to deliver phosphatidylethanolamine-binding protein 1 (PEBP1) mRNA for inhibiting ferroptosis in vascular smooth muscle cells (VSMCs) and preventing AAA progression. Differential gene expression analysis of the AAA transcriptomic dataset GSE57691 identified 243 differentially expressed genes (DEGs), intersecting with 12 ferroptosis-related genes. Single-cell analysis of dataset GSE237230 highlighted PEBP1 as a key gene in VSMCs. Overexpression of PEBP1 in VSMCs enhanced proliferation, reduced reactive oxygen species (ROS) and iron levels, and inhibited apoptosis and ferroptosis via the NRF2/GPX4 axis. The engineered biomimetic nanovesicles demonstrated significant uptake by VSMCs and effective delivery of PEBP1 mRNA. In vivo studies confirmed that these nanovesicles substantially inhibited AAA progression in mice. This study presents a novel bioengineering approach for AAA treatment by targeting ferroptosis through PEBP1 mRNA delivery, offering a promising molecular strategy for the prevention and management of AAA.
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Nano Today
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2020
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IF 16.907
Xinyu Shen,Ruonan Ma,Yixin Huang,Lei Chen,Zhuobin Xu,Dandan Li,Xiangqin Meng,Kelong Fan,Juqun Xi,Xiyun Yan,Hyun Koo,Yili Yang,Jing Jiang,Lizeng Gao
Antibacterial nanomaterials provide promising alternative strategies to combat the global challenge of bacterial infection due to deteriorating resistance. However, few have been applied for intracellular bacteria killing or in vivo therapy due to potential cytotoxicity and poor biocompatibility. Here we present a strategy to generate formula suitable for in vivo anti-infective therapy by decocting antibacterial nanomaterial. An aqueous formula containing ferrous iron and polysulfide (Fe(II)S n aq) is prepared by a decoction procedure using nano-iron sulfide (nFeS) as raw substance. Theoretical calculation indicated that replacement of a sulfur atom by an oxygen atom occurred, resulting in polysulfide release and iron dissolution. The Fe(II)S n aq decocted from nFeS induced bacterial death with ferroptosis-like hallmarks, including iron enrichment, lipid peroxidation, and glutathione (GSH) depletion. The antibacterial action of Fe(II)S n aq was dependent on ferrous iron, which could be inhibited by iron chelators, ferroptosis inhibitors, and GSH, while the polysulfide prevented ferrous iron oxidation and counteracted GSH. Furthermore, Fe(II)S n aq not only killed up to 99 % of planktonic bacteria within 5 min, but also suppressed up to 90 % of intracellular Staphylococcus aureus without triggering cytotoxicity to host cell. Administration of Fe(II)S n aq achieved equivalent therapeutic effect to vancomycin for infectious pneumonia treatment and significantly prolonged the survival period of septic mice. These results indicate that aqueous ferrous polysulfide can induce ferroptosis- like death in bacteria and may be formulated as an antibacterial alternative for anti-infection therapy.
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BIOCHEMICAL PHARMACOLOGY
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2021
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IF 5.858
Yi Wang,Zhigang Wang,Zhengping Wu,Menglin Chen,Dong Dong,Pei Yu,Danyi Lu,Baojian Wu
The molecular events underlying aristolochic acid (AA) nephropathy are poorly understood, and specific therapies for treatment of AA nephropathy are still lacking. Here we aimed to investigate a potential role of REV-ERBα and ferroptosis in renal injury induced by aristolochic acid I (AAI), a typical AA. The regulatory effects of REV-ERBα on AAI-induced renal injury were determined using kidney-specific Rev-erbα knockout mice . Ferroptosis was assessed based on measurements of iron, GSH, and GPX4 . Targeted antagonism of REV-ERBα to alleviate AAI-induced renal injury and ferroptosis was assessed using the small molecule antagonist SR8278. mRNAs and proteins were quantified by qPCR and Western blotting , respectively. We first showed that REV-ERBα was upregulated and its target BMAL1 was downregulated in the kidney of mice with AAI nephropathy. Upregulation of REV-ERBα protein was confirmed in aristolactam I (ALI, a nephrotoxic metabolite of AAI)-treated mRTECs. We also observed enhanced ferroptosis (known to be regulated by REV-ERBα) in mice with AAI nephropathy and in ALI-treated mRTECs. Kidney-specific knockout of Rev-erbα reduced the sensitivity of mice to AAI-induced ferroptosis and renal injury. Furthermore, knockdown of Rev-erbα by siRNA or SR8278 (a REV-ERBα antagonist) treatment attenuated ALI-induced ferroptosis in mRTECs. Moreover, REV-ERBα antagonism by SR8278 alleviated ferroptosis and renal injury caused by AAI in mice. In conclusion, we identify REV-ERBα as a regulator of AAI-induced renal injury via promoting ferroptosis. Targeting REV-ERBα may represent a promising approach for management of AAI nephropathy.
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Frontiers in Toxicology
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2025
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IF 4.6
Liu-Dan Liang,Xiao-Yue Zhao,Li Li,Sheng Liang,Jin-Min Zhang,Jian-Nan Lv,Feng-Lian Deng,Chun-Lei Lu,Qian Li,Qi-Wen Huang,Mei-Jin Huang,Hui-Xin Peng
Aluminum is toxic to both humans and animals. Exposure to AlCl 3 can lead to kidney function damage, yet the specific underlying mechanism remains elusive. This study aimed to investigate whether ferroptosis is involved in the renal toxicity induced by AlCl 3 exposure in mice and to elucidate its potential molecular mechanism. Forty-eight C57BL mice were randomly assigned to six groups, with eight mice in each group: a control group, low -, medium -, and high - dose aluminum exposure groups, a ferroptosis inhibitor group, and a ferroptosis inhibitor + high - dose aluminum exposure group. Mice in the aluminum exposure groups received intraperitoneal injections of different doses of AlCl 3 solution for 4 weeks (5 times per week), while the ferroptosis inhibitor group was intraperitoneally injected with Fer - 1 for 4 weeks (2 times per week). After the experimental period, multiple indicators were examined. The results demonstrated that AlCl 3 exposure impaired the renal function and structure of mice. It also led to an increase in lipid peroxidation products, Fe 2+ , and Al content in renal tissue. Moreover, the expression levels of genes and proteins such as GPX4 and Nrf2 were decreased, whereas the expression levels of the ACSL4 gene and protein were increased.However, after pretreatment with Fer - 1, the aforementioned indicators were ameliorated. Specifically, the expression of ACSL4 decreased, and the expression of GPX4 and other related factors increased.In conclusion, this study suggests that AlCl 3 exposure may trigger ferroptosis in renal tissue cells by inhibiting the NRF2 pathway, thereby causing kidney function damage in mice. These findings provide a novel perspective on the mechanism of AlCl 3 - induced renal toxicity.
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PHYTOMEDICINE
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2025
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IF 8.3
Mengdi Cui,Yi An,Jingling Zhao,Miaoxin Hui,Zhili Xiong,Bing Guan,Yinfeng Shen,Yinshui Zou,Chengyin Li,Rui Wang
Background: Acute kidney injury (AKI) is a leading complication of sepsis, necessitating the exploration of novel treatment modalities. The traditional Chinese medicine Dahuang Gancao Decoction (DHGC) has potential in the treatment of sepsis-associated acute kidney injury (SA-AKI). However, its specific mechanisms require further investigation. Purpose: This study aimed to validate the antiferroptotic effects of DHGC in the treatment of SA-AKI in vivo and in vitro . Methods: C57BL/6 mice and C57BL/6-background sirtuin-3 (SIRT3) -/- mice were induced with Reagents Lipopolysaccharide (LPS), while normal and si-SIRT3 human proximal tubular epithelial (HK-2) cells were induced with erastin to establish a ferroptosis phenotype, followed by DHGC treatment. First, the DHGC components were identified via liquid chromatography-tandem mass spectrometry (LC‒MS/MS), and the potential active components were further screened through comparison with the high-performance liquid chromatography (HPLC) reference standards. Ferroptosis levels and the protective mechanisms of DHGC in vivo and in vitro were evaluated using biochemical assays, transmission electron microscopy, immunohistochemistry, immunofluorescence, and Cell Counting Kit-8 (CCK-8) assays. Key pathways were identified by RNA-seq and validated via enzyme-linked immunosorbent assay (ELISA) and western blotting. Finally, the potential active components were subjected to molecular docking with SIRT3 to select candidate monomers for subsequent in vitro functional validation. Results: LPS was used to induce SA-AKI in mice, and erastin was used to induce ferroptosis in HK-2 cells. DHGC can improve renal function, increase cell viability, and reverse abnormal changes in key ferroptosis indicators. Mechanistically, the expression levels of SIRT3/nuclear factor erythroid-2 related factor 2 (NRF2) pathway-associated proteins were downregulated, and NRF2 nuclear translocation was restricted after modeling; in contrast, DHGC upregulated the expression of SIRT3/NRF2 pathway-related proteins, promoted NRF2 nuclear translocation, and activated downstream glutathione peroxidase 4 (GPX4) expression. Importantly, DHGC failed to improve the above indicators in SIRT3-deficient models. Potential active components of DHGC were screened via HPLC reference standard comparison, and subsequent molecular docking with SIRT3 identified candidate monomers. These monomers exerted ferroptosis-inhibiting effects consistent with those of the parent compound DHGC. Conclusions: The present study offers the first demonstration that DHGC retards SA-AKI progression through stimulating SIRT3-driven deacetylation of NRF2, promoting NRF2 nuclear translocation, and inhibiting ferroptosis. These findings suggest that DHGC is a potential therapeutic candidate for SA-AKI, warranting further clinical investigation.
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