Science China-Life Sciences
·
2026
·
IF 9.6
Wang Bao,Fu Junpeng,Qian Jian,Wei Yuang,Bao Meiling,Miao Haoqi,Zhao Xinzhe,Shao Kezheng,Song Yuan,Tan Ruoyun,Li Jie,Shao Pengfei
Clear cell renal cell carcinoma (ccRCC) exhibits aberrant lipid synthesis, yet how this metabolic reprogramming influences ferroptosis—a form of regulated cell death driven by lipid peroxidation—remains poorly understood. This study demonstrates that the key lipid transcription factor SREBP1 acts as a master regulator that promotes ccRCC progression by suppressing ferroptosis. Using SREBP1-knockdown cell models, we found that SREBP1 depletion enriches ferroptosis-related pathways and enhances ferroptosis sensitivity, as evidenced by elevated mitochondrial ROS, labile iron pool, PE-OOH levels, and characteristic mitochondrial alterations. Mechanistically, SREBP1 transcriptionally represses the pro-ferroptotic gene ACSL4 while simultaneously activating the lipid-synthesis gene FASN . Rescue experiments revealed that modulating either ACSL4 or FASN alone only partially reverses the ferroptosis phenotype induced by SREBP1 loss, whereas dual manipulation of both genes fully restores ferroptosis resistance. Metabolomic analyses showed that ACSL4 and FASN converge to regulate the cellular PUFAs/MUFAs ratio, which in turn feeds back to modulate SREBP1 nuclear translocation, thereby establishing a self-reinforcing positive-feedback loop. Clinically, low ACSL4 expression correlates with advanced tumor stage and poor patient survival. In vivo, SREBP1 promotes tumor growth by inhibiting ferroptosis via the ACSL4 / FASN axis. Collectively, our findings reveal that SREBP1 drives ccRCC malignancy through a dual-pronged mechanism—repressing ACSL4 and activating FASN—to alter the PUFAs/MUFAs balance and establish a feed-forward loop that sustains ferroptosis suppression. ACSL4 represents a potential prognostic biomarker, and targeting the SREBP1-ACSL4 / FASN axis offers a promising therapeutic strategy for ccRCC.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Xingjie Zhuo,Shuxian Ding,Jinhua Li,Mingcong Deng,Xinyue Zhang,Weijun Yang,Lili Gu,Qin Li
Background Ischemic stroke (IS) is a major global cause of disability and death, with its complex pathophysiology posing a significant challenge for effective therapy. Although flavonoids from Ziziphora clinopodioides Flavonoids (ZCF) have demonstrated neuroprotective potential, their comprehensive mechanisms of action remain incompletely understood. Objective The purpose of this study is to systematically elucidate the improvement effect of ZCF on ischemic stroke and its potential mechanism by integrating multi-omics analysis and in vitro and in vivo experimental verification. Methods In this study, the neuroprotective mechanism of ZCF on MCAO/R-treated SD rats and OGD/R-treated PC12 cells was studied by combining transcriptomics, non-targeted metabolomics, and molecular biology verification (Western blot, q-PCR, immunofluorescence, etc.). The key role of FUNDC1 in this pathway was verified by siRNA knockdown. Results ZCF administration significantly improved neurological function, reduced cerebral infarction volume, and reduced neuronal apoptosis. Integrated transcriptomics and metabolomics analysis found that ZCF reversed disease-related changes, and its core effects were the mitophagy and ferroptosis pathways. Mechanistically, ZCF alleviates pathological TDP-43 aggregation, activates FUNDC1-mediated mitophagy, and inhibits ferroptosis. Crucially, siRNA knockdown of FUNDC1 eliminated these protective effects. Conclusion ZCF improves ischemic stroke by enhancing FUNDC1-dependent mitophagy to remove pathological TDP-43, thereby inhibiting the mechanism of ferroptosis.
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2026
·
IF 17.3
Yilin Huang,Huan Ru,Chanlin Fang,Shanshan Di,You Weng,Mingrong Qian,Yuanxiang Jin
Abstract 6PPD, as an antioxidant in tire rubber, constitutes an emerging pollutant together with nanoplastics (NPs) widely present in the environment. This study explored the potential combined toxicity risk of 6PPD and 50 nm polystyrene nanoplastics (PS-NPs) to aquatic ecosystems. The study found that the presence of PS-NPs altered the physicochemical behavior of 6PPD and was associated with reduced cardiac accumulation of 6PPD and its oxidation product 6PPD-Q. The experiment showed that 6PPD activated the p53 signaling pathway by upregulating the expression of GRK5, thereby inhibiting the expression of SLC7A11 and GPX4, leading to increased ROS, iron overload, lipid peroxidation, and mitochondrial damage in zebrafish heart and rat cardiomyocytes (H9C2), thereby triggering ferroptosis. After coexposure of PS-NPs and 6PPD, physicochemical interactions between PS-NPs and 6PPD altered the colloidal state and environmental behavior of the mixture, while the cardiac levels of both 6PPD and 6PPD-Q were reduced, accompanied by weakened ferroptosis-related responses. This study revealed the cardiotoxic mechanism of 6PPD and the mitigation effect of PS-NPs after coexposure, providing a basis for environmental pollution risk assessment.
✓ 已验证
DOI
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2026
·
IF 8
Xie-Huang Sheng,Lin-Song Teng,Xin-Hui Wang,Li-Qi Jiang,Xue-Cheng Sun,Jin-Long Mao,Lei Zhang
Cardiovascular diseases arise from intertwined cell-death and stress-response pathways, underscoring the need for therapeutics that extend beyond single-target mechanisms. Seeking drug-repurposing opportunities within existing cardiovascular agents, we screened clinically explored compounds for unrecognized cytoprotective activity and identified the hERG/Kv11.1 activator NS-1643—originally developed as an antiarrhythmic candidate—as a potent ferroptosis inhibitor. NS-1643 broadly suppressed GPX4 inhibitor–induced ferroptotic death across diverse cell types, whereas other hERG modulators were inactive, and neither pharmacologic blockade nor genetic silencing of hERG altered its efficacy, demonstrating that its protective mechanism is independent of ion-channel modulation. Mechanistic profiling showed that NS-1643 does not restore canonical ferroptosis-defense systems, but instead operates as a direct lipid-peroxyl radical trapper, supported by radical-scavenging assays and density functional theory revealing an energetically favorable hydrogen-atom transfer mediated by its ortho-amino–phenolic motif. In a murine model of doxorubicin (DOX) cardiotoxicity, NS-1643 markedly improved survival, preserved systolic performance, and reduced myocardial injury, fibrosis, and 4-HNE accumulation, whereas the comparator hERG agonist NS-3623 conferred no benefit. These findings reposition NS-1643 as a dual-mechanism, ferroptosis-targeting cardioprotective agent and illustrate how drug repurposing can reveal multi-target therapeutic potential within existing cardiovascular chemical space, offering a promising strategy to mitigate anthracycline-induced cardiac injury.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2026
·
IF 11.8
Jiarong Liang,Xiangkun Li,Si Wang,Zhonghui Ma,Fei Kuang,Mengdie Duan,Zhiyi Wang
Conventional photocatalysis is fundamentally constrained by the competitive nature of excited-state dynamics, which typically restricts utilization to a single excitonic channel. Consequently, simultaneously harvesting both excitons to maximize reactive oxygen species (ROS) generation remains a formidable challenge in cancer theragnostic. Herein, an ionic engineering strategy is developed to overcome this excitonic bottleneck by constructing sulfonated covalent organic frameworks (BD-SO 3 -COF) via backbone quaternization. This specific ionic modulation imparts a strong push-pull electronic landscape that fundamentally reshapes excited-state dynamics. Mechanistically, the sulfonate moieties suppress the parasitic radiative recombination of singlet excitons (S 1 ) to boost superoxide anion (O 2 •− ) generation specifically at the electron-deficient quaternized pyridine rings (redox sites), while simultaneously populating long-lived triplet excitons (T 1 ) on the porphyrin macrocycles that activate molecular oxygen via an efficient Dexter energy transfer pathway to produce singlet oxygen ( 1 O 2 ). Capitalizing on this site-specific dual-state activation, the engineered COF triggers robust photodynamic therapy (PDT) and induces catastrophic lipid peroxidation, effectively driving cancer cells into ferroptosis. In vivo assessments confirm that this synergistic PDT-ferroptosis strategy achieves potent tumor regression with minimal systemic toxicity. This work elucidates the critical role of specific active-site engineering in ionic COFs and provides a paradigm for designing molecular photosensitizers for multi-modal cancer therapy.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2026
·
IF 12.4
Luo Zhao,Zilin Ma,Yange Du,Ziqing Wang,Liulu Wu,Yangyang Zhang,Xinxin Liu,Mengya Niu,Yuanyuan Li,Lei Wang
Inflammatory bowel disease (IBD) is closely associated with macrophage dysregulation, particularly insufficient anti-inflammatory M2 macrophages. However, current therapies mainly emphasize M2 polarization, with limited attention to the ferroptotic vulnerability of M2 macrophages under oxidative IBD conditions. Here, we developed an oral nanoarray hydrogel (BAN@Ca) designed to restore immune homeostasis via a synergistic strategy of blocking ferroptotic pathways and remodeling macrophage phenotypes. Constructed by crosslinking bilirubin-alginate self-assembled nanoparticles (BAN) with calcium ions (Ca 2+ ), BAN@Ca features dual pH/enzyme-responsiveness, enabling colon-specific degradation and overcoming the diffusion barriers typical of conventional hydrogels to achieve rapid dissociation at the disease site. Mechanistically, the released BAN specifically targets M2 macrophages and leverages bilirubin to scavenge reactive oxygen species (ROS) and upregulate the GSH/GPX4 axis, thereby effectively blocking lipid peroxidation-driven ferroptosis and ensuring cell survival. Simultaneously, co-released Ca 2+ activates the PI3K/AKT signaling pathway to robustly drive the reprogramming of pro-inflammatory M1 macrophages into the M2 phenotype, replenishing the M2 pool. Both in vitro and in vivo studies confirm that BAN@Ca significantly ameliorates colitis symptoms and promotes mucosal healing. This study demonstrates that the synergistic modulation of macrophage polarization and ferroptosis susceptibility represents a highly effective and novel therapeutic strategy for IBD.
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2026
·
IF 8.7
Xuyan Hu,Hao Zhuang,Ke Gao,Yaqi Zhu,Fan Gao,Haili Wang,Zijin Zhang,Baoqiang Su,Yubing Zhang,Cailiang Shen
Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents, featuring aggressive tumor growth and early metastasis. Current treatments, including chemotherapy and surgery, are often limited by chemoresistance and postoperative infections. Ferroptosis has emerged as a strategy to overcome chemoresistance, as it is intrinsically iron-dependent, whereas OS often exhibits dysregulated iron metabolism. Halicin, a broad-spectrum antimicrobial known to regulate iron metabolism in bacteria, was found to be a ferroptosis inducer for OS in this study. However, its therapeutic efficacy is likely hampered by rapid systemic clearance and poor tumor retention. Accordingly, we developed Halicin@Gel, an injectable hyaluronic acid hydrogel designed for localized and prolonged release. The structure, injectability, drug release behavior, biocompatibility, antibacterial activity, and antitumor efficacy of this system were characterized and evaluated in vitro and in vivo. Halicin@Gel exhibited excellent antibacterial activity and significantly inhibited OS cell proliferation and migration in vitro. Mechanistically, Halicin@Gel increased intracellular ROS levels and was associated with p38 MAPK activation, as well as ferroptosis- and apoptosis-related changes. In vivo, Halicin@Gel significantly inhibited tumor growth with minimal systemic toxicity, confirming its therapeutic potential. Thus, these findings support Halicin@Gel as a promising localized therapeutic platform with combined antitumor and antibacterial functions for OS treatment.
✓ 已验证
DOI
PubMed
高影响因子
Scientific Reports
·
2026
·
IF 4.9
Wang Ying,Zhang Qi,Liu Jiahui,Kuang Hongying,Feng Xiaoling
Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder among women of childbearing age and the leading cause of anovulatory infertility worldwide, with the death of granulosa cells implicated in its pathogenesis. However, the mechanisms underlying granulosa cell death remain unclear. Limited research has explored the association between GATA binding factor 1 (GATA1) and adverse pregnancy outcomes, yet its role in PCOS is still elusive. This study established an in vivo PCOS model via dehydroepiandrosterone administration in mice and used ovarian-like KGN cells to explore granulosa cell function. Results showed elevated ovarian GATA1 expression in PCOS mice. Functionally, GATA1 overexpression in KGN cells increased lipid reactive oxygen species, malondialdehyde, and iron, while reducing glutathione. Notably, all these effects of GATA1 were mitigated by a ferroptosis inhibitor Ferrostatin-1. Furthermore, GATA1 knockdown alleviated lipid peroxidation and iron overload in KGN cells induced by a ferroptosis inducer Erastin. Mechanistically, GATA1 directly bound the transferrin receptor (TFRC) promoter to enhance its transcription. Additionally, TFRC overexpression counteracted GATA1 knockdown’s protective effects against Erastin-induced ferroptosis. Collectively, GATA1 promotes granulosa cell ferroptosis via TFRC transcriptional activation, contributing to PCOS pathogenesis. GATA1 regulatory pathways may serve as potential therapeutic targets for PCOS.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FASEB JOURNAL
·
2026
·Vol. 40
·期 14
·e72154
·
IF 4.3
Ya‐Ping Li,Fei‐Hong Huang,Meng‐Ting Wu,Meng‐Yi Chen,Yong‐Ping Wen,Xiang Li,Lu Yu,An‐Guo Wu,Jian‐Ming Wu,Xiao‐Gang Zhou
Ferroptosis contributes to aging‐associated functional decline, yet compounds with robust organismal efficacy and defined upstream regulatory mechanisms remain limited. Here, we established a diethyl maleate (DEM)‐induced glutathione depletion model in wild‐type (N2) Caenorhabditis elegans as a survival‐based screening platform and identified syringaresinol (Syr) as a leading hit from an in‐house small‐molecule library. In nematodes, Syr improved survival under DEM challenge, reduced lipid peroxidation, reactive oxygen species (ROS), and malondialdehyde levels, and alleviated age‐associated oxidative lipid stress and iron imbalance during natural aging, accompanied by extended lifespan and improved healthspan‐related phenotypes. In primary human foreskin fibroblasts, Syr conferred dose‐dependent protection against RSL3‐ or erastin‐induced ferroptosis, preserved cellular integrity, suppressed lipid peroxidation and ROS, and restored expression of GPX4, SLC7A11, and ferritin. In two senescence models, Syr also attenuated senescence‐associated phenotypes and ferroptosis‐related oxidative lipid stress, concomitant with recovery of GPX4 expression. Network‐based prediction and functional perturbation identified HIF‐1α as a candidate mediator of Syr‐associated cytoprotection. HIF‐1α knockdown weakened Syr‐mediated protection and largely prevented GPX4 restoration, whereas GPX4 knockdown did not alter HIF‐1α abundance. These findings support a functional HIF‐1α–GPX4 defense axis in fibroblasts, while direct transcriptional regulation remains to be clarified. Overall, Syr attenuates ferroptosis‐relevant oxidative lipid stress and aging‐associated phenotypes in C. elegans and human fibroblast models, supporting further mechanistic and mammalian in vivo validation. A 220‐compound screen in DEM‐challenged C. elegans identified syringaresinol (Syr) as a lead protective compound. Syr alleviated aging‐ and ferroptosis‐associated phenotypes in C. elegans and human foreskin fibroblasts by reducing lipid peroxidation, ROS accumulation, MDA levels, labile Fe 2+ , cell death, and SA‐β‐gal activity, while restoring GPX4/SLC7A11/ferritin‐associated defense responses. The proposed mechanism suggests that Syr attenuates senescence‐associated functional decline through a HIF‐1α‐associated GPX4 protective axis. The dashed arrow denotes a hypothesized mediator or interaction that remains to be experimentally validated.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Yan Gong,Qiurong Sun,Gao He,Jiarui Wang,Dequan Xiao,Lile Dong
Insufficient intracellular Fe 2+ ions availability and hypoxic tumor microenvironment significantly hamper the efficiency of ferroptosis. There is an urgent need for breakthrough research in the development and delivery of ferroptosis inducers and the reprogramming of the immune microenvironment. Herein, Ti 3 FeBi 5 O 15 (TFBO) piezoelectric nanosheets were engineered to amplify ferroptosis and trigger immunogenic cell death via ultrasound (US) activation. TFBO nanosheets feature a narrow bandgap (2.03 eV) and high piezoelectric coefficient (d 33 = 22.1 pm V −1 ), enabling efficient electron-hole separation under US irradiation. Notably, TFBO nanosheets generate an internal piezoelectric field that promotes Fe 3+ to Fe 2+ conversion and ·OH generation from H 2 O under US irradiation, while simultaneously depleting intracellular GSH under US irradiation, leading to lipid peroxidation and GPX4 suppression. Importantly, TFBO nanosheets activate immunogenic cell death (ICD), stimulating antitumor immune responses. Therefore, combined with its high biocompatibility, effective tumor inhibiting performance, and minimal systemic toxicity, TFBO represents a mechanistically distinct and translationally promising ferroptosis amplifier for tumor therapy.
✓ 已验证
产品关联
DOI
高影响因子
MATERIALS & DESIGN
·
2025
·
IF 7.9
Jingxian Mao,Xueping Huang,Yang Liu,Ying Wang,Dandan Li,Zhuobin Xu,Xuebing Yan,Tingting Liu,Huihui Wang
Both reactive oxygen species (ROS) and ferroptosis are recognized for their pivotal regulatory roles in tumor survival. However, the hypoxic and high glutathione (GSH) environment within tumors presents a significant barrier to these therapeutic strategies. In this study, we have developed a novel gold-doped carbon-dotted nanozyme (Au-CDs) exhibiting multi-enzyme-like activities, which effectively alleviate tumor hypoxia and achieve the self-enhanced combined treatment effect of chemodynamic (CDT) and photodynamic therapy (PDT) independent of oxygen. Furthermore, it effectively depletes GSH to achieve a robust ROS amplifier. The synthesized Au-CDs have demonstrated efficacy in inducing ROS release, promoting lipid peroxidation accumulation and reducing the GSH levels, resulting in the inhibited proliferation of tumor cells in vitro . In a xenograft model, Au-CDs effectively inhibited the tumor growth of nude mice. In terms of molecular mechanism, Au-CDs were able to upregulate transferrin receptor 1 (TFR1) expression and increase the Fe 2+ content, and finally to induce the tumor related ferroptosis, which was more significant in combination with self-enhanced PDT. The biosafety assessment demonstrated Au-CDs had no significant toxicity in the major organs of mice. Taken together, these findings suggested Au-CDs as a novel and safe nanozyme have great potential to be utilized in combination therapies in cancer.
✓ 已验证
产品关联
DOI
高影响因子
NEW JOURNAL OF CHEMISTRY
·
2025
·
IF 2.5
Hanyu Yao,Ruixuan Ji,Xiaoyi Song,Bin Yang,Yin Lv,Zhong Wei
Ferroptosis, a recently recognized form of non-classical programmed cell death (PCD), leads to impaired cellular structure and integrity due to the accumulation of lipid peroxidation products (LPO). However, single treatment ferroptosis often fails to achieve optimal tumor treatment outcome. Therefore, we constructed a multi-synergistic treatment strategy based on ferroptosis, that is more conducive to tumor therapy. In this study, we constructed a metal organic framework (MOF) loaded with glucose oxidase (GOx) and doxorubicin (DOX), denoted as Fe(Ⅲ)-RSSR@DOX@PEG-GOx. Fe(Ⅲ)-RSSR@DOX@PEG-GOx was synthesized through coordination between Fe3+ and disulfide-containing ligands scavenged GSH and downregulate glutathione peroxidase 4 (GPX4), thereby triggering ferroptosis. The GOx catalyzes glucose into abundant H2O2, promoting the Fenton reaction which results in excessive ROS formation within tumors. The accumulation of ROS can further enhance the process of ferroptosis, while the massive consumption of glucose constitutes a synergistic situation of “starvation treatment”. The smart biomimetic nanoplatform integrates ferroptosis, chemotherapy, and starvation therapy, providing a potential anti-tumor strategy to achieving multi-effect synergistic tumor treatment.
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）