FREE RADICAL BIOLOGY AND MEDICINE
·
2026
·
IF 8
Baisheng Sun,Lingxin Liu,He Zhang,Xiaoli Wang,Lanlan Chen,Yan Shen,Hui Liu,Hongjun Kang,Feihu Zhou
Post-traumatic septic myocardial dysfunction (PT-SIMD) is a life-threatening condition with high mortality and no specific treatment. Ferroptosis, an iron-dependent regulated cell death pathway driven by lipid peroxidation, has been implicated in septic cardiac injury, yet the endogenous mechanisms that counteract this process remain poorly understood. We aimed to identify novel cardioprotective regulators of ferroptosis in PT-SIMD using unbiased proteomics and to investigate whether the GLP-1 receptor agonist semaglutide (SEMA) confers protection through modulation of mitochondrial E3 ubiquitin ligases. In a rat model combining limb crush injury and cecal ligation and puncture (CLP), PT-SIMD was accompanied by marked myocardial ferroptosis, evidenced by elevated ACSL4, reduced GPX4/FSP1, and 4-HNE accumulation. Quantitative 4D-DIA proteomic profiling identified March5, a mitochondrial E3 ubiquitin ligase, as significantly downregulated. In primary neonatal rat ventricular myocytes, LPS exposure suppressed March5 expression in a dose- and time-dependent manner. Knockdown of March5 using siRNA exacerbated LPS-induced ferroptosis, increasing ACSL4 protein levels, labile Fe2+, and lipid peroxidation. Notably, SEMA treatment upregulated March5 expression, attenuated ACSL4 accumulation, and ameliorated ferroptotic injury. Crucially, siRNA-mediated silencing of March5 in cardiomyocytes completely abolished the anti-ferroptotic and cytoprotective effects of SEMA. Collectively, March5 functions as a critical endogenous suppressor of ferroptosis in PT-SIMD by negatively regulating ACSL4. Semaglutide exerts its cardioprotective action via March5-dependent inhibition of the ACSL4 ferroptosis axis, highlighting a promising therapeutic strategy for sepsis-associated myocardial dysfunction.
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高影响因子
ANALYTICAL CHEMISTRY
·
2026
·Vol. 98
·期 30
·22418-22428
·
IF 7.3
Bin Yidong,Huang Lixian,Li Caiying,Zhao Jingjin,Hu Shengqiang,Zhao Shulin,Huang Yong,Zhang Liangliang
As
an emerging form of regulated cell death, ferroptosis
has been
identified as a key contributor to the pathogenesis of several diseases.
Superoxide anion (O •– 2 ), a key reactive oxygen species, is closely
associated with ferroptosis-mediated acute liver injury (ALI). The
development of in situ, real-time imaging tools capable of visualizing
O •– 2 will benefit the early diagnosis and therapeutic intervention of
ferroptosis-mediated ALI. In this work, we designed and synthesized
a photoacoustic (PA) probe, Rho-DOH, based on a rhodamine scaffold,
for the specific detection of O •– 2 . Rho-DOH exhibits a highly
sensitive, selective, and fast PA response toward O •– 2 , characterized
by a large bathochromic shift of 125 nm and an activation fold of
up to 29-fold. Cellular experiments demonstrate that Rho-DOH enables
high-contrast PA imaging of endogenous O •– 2 in cells. Moreover, Rho-DOH
was successfully applied to detect the ferroptosis-mediated ALI and
to evaluate therapeutic responses through its O •– 2 -responsive PA
imaging signal. These findings position Rho-DOH as a promising molecular
imaging tool, offering robust support for the accurate diagnosis and
treatment of ferroptosis-associated liver injury.
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高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Ludong Tan,Xiaodong Bai,Peiyuan Yu,Tinghan Jiang,Zhe Jin
Artemisia capillaris extract alleviates acetaminophen-induced liver injury by inhibiting ferroptosis. • Capillarisin is identified as the primary bioactive constituent responsible for the hepatoprotection. • Capillarisin directly binds to and inhibits Glycogen Synthase Kinase 3β (GSK3β). • Inhibition of GSK3β by Capillarisin activates the Nrf2-mediated anti-ferroptotic pathway. • This study reveals a novel molecular mechanism for a traditional hepatoprotective herb. Background Acetaminophen (APAP) overdose is a leading cause of acute liver failure worldwide, characterized by oxidative stress-driven hepatocyte necrosis. Recent evidence implicates ferroptosis, an iron-dependent cell death, as a critical pathogenic event. Artemisia capillaris Thunb. (ACE) is a traditional hepatoprotective herb; however, its bioactive constituents and molecular targets regulating ferroptosis remain elusive. Purpose This study aimed to identify the bioactive compounds of ACE and elucidate the molecular mechanism underlying its protective effect against APAP-induced hepatotoxicity, with a specific focus on the ferroptosis pathway. Methods We integrated multi-omics, network pharmacology, and rigorous biophysical assays to decipher the protective mechanism. The ethanol extract of A. capillaris was chemically characterized using UPLC-LTQ-Orbitrap MS. An APAP-induced acute liver injury model in C57BL/6 mice and primary mouse hepatocytes were employed. Transcriptomics (RNA-seq) was utilized to identify key signaling pathways. The direct physical interaction between the active compound and its target was validated using Microscale Thermophoresis (MST), Cellular Thermal Shift Assay (CETSA), Drug Affinity Responsive Target Stability (DARTS), and molecular dynamics (MD) simulations. Functional validation was performed using gene overexpression and specific inhibitors. Results ACE pretreatment significantly attenuated APAP-induced liver injury, inflammation, and oxidative stress in mice. Transcriptomic profiling identified ferroptosis as a primary target pathway. Through chemical screening, we identified Capillarisin as the key bioactive coumarin responsible for this effect. Capillarisin treatment effectively suppressed lipid peroxidation, iron overload, and the expression of ferroptotic markers (COX2, ACSL4) while restoring GPX4 levels both in vivo and in vitro . Mechanistically, we demonstrated that Capillarisin acts as a direct inhibitor of Glycogen Synthase Kinase 3β (GSK3β). Capillarisin binds stably to the ATP-binding pocket of GSK3β ( K d = 0.87 µM), thereby inhibiting its kinase activity. This inhibition blocks the phosphorylation-dependent degradation of Nrf2, promoting its nuclear translocation and the subsequent transcriptional activation of anti-ferroptotic genes ( Gpx4, Slc7a11 ). Overexpression of GSK3β or pharmacological inhibition of Nrf2 abolished the protective effects of Capillarisin. Conclusion Our study reveals a novel mechanism whereby Capillarisin alleviates APAP-induced hepatotoxicity by directly targeting GSK3β to activate the Nrf2-mediated anti-ferroptosis defense. These findings provide a rigorous scientific basis for the ethnopharmacological use of Artemisia capillaris and highlight Capillarisin as a promising lead candidate for targeting GSK3β in the treatment of drug-induced liver injury. Download: Download high-res image (228KB) Download: Download full-size image
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Advanced Science
·
2026
·
IF 14.1
Liang Xu,Wanying Xiang,Xinyue Wang,Yue Pan,Jing Gao,Jiezhen Yang,Yufei Wang,Zhipu Zhu,Man Tong,Lei Jin,Yan Ye
Platinum-based chemotherapy resistance remains a major obstacle in gastric cancer (GC) treatment. Through integrated transcriptomic profiling of cisplatin-resistant xenografts and pharmacogenomic interrogation of the NCI-60 dataset, we identified Prohibitin-2 (PHB2) as a previously unrecognized determinant of chemoresistance. PHB2 was consistently upregulated in resistant tumors and associated with poor clinical outcomes. Mechanistically, PHB2 binds the lipid-metabolic enzyme ACSL3 through a defined AMP-binding–domain interface (residues W244/H254/E260), enhancing ACSL3 activity to promote monounsaturated fatty acid incorporation into phospholipids. This phospholipid remodeling suppresses lipid peroxidation and establishes a ferroptosis-resistant state. Structure-based virtual screening of an FDA-approved drug library nominated the CXCR4 antagonist Mavorixafor as a potent inhibitor of the PHB2–ACSL3 interaction. Mavorixafor disrupted lipid remodeling, restored ferroptosis susceptibility, and resensitized cisplatin-resistant GC in cell line–derived xenografts (CDOs) and patient-derived organoids (PDOs). The therapeutic effect was abrogated by the ferroptosis inhibitor Liproxstatin-1, confirming ferroptosis dependence. Collectively, our findings define a PHB2–ACSL3 lipid-metabolic axis that drives ferroptosis escape and identify Mavorixafor repurposing as an immediately translatable strategy to overcome cisplatin resistance in treatment-refractory GC.
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MATERIALS & DESIGN
·
2026
·
IF 8.2
Linjun Yang,Xuhui Fan,Weicheng Pan,Yao Jin,Jianle Wang,You Wang,Han Wang,Zhijun Hu
Composition-engineered Cu-doped ZIF-8 was designed for OA therapy. • Cu@ZIF-8 reduced oxidative stress and lipid peroxidation in chondrocytes. • Cu@ZIF-8 suppressed ferroptosis and preserved ECM homeostasis. • Intra-articular Cu@ZIF-8 attenuated OA progression in rats. Engineering metal–organic framework (MOF)-based materials with tunable composition and biological function offers a promising strategy for regulating pathological oxidative microenvironments. Herein, a composition-engineered copper-doped zeolitic imidazolate framework-8 nanoplatform, Cu@ZIF-8, was designed to modulate oxidative stress-associated lipid peroxidation and chondrocyte ferroptosis for osteoarthritis (OA) therapy. The incorporation of copper into the ZIF-8 framework enabled homogeneous elemental distribution while preserving the crystalline structure and high specific surface area of the MOF platform. In H 2 O 2 - and RSL3-induced chondrocyte injury models, Cu@ZIF-8 reduced intracellular ROS accumulation, alleviated lipid peroxidation, preserved mitochondrial membrane potential, restored GPX4/SLC7A11 expression, and maintained extracellular matrix homeostasis. Mechanistic studies suggested that Cu@ZIF-8-mediated ferroptosis suppression was associated, at least in part, with modulation of p38 MAPK/AKT signaling. In a surgically induced rat OA model, intra-articular administration of Cu@ZIF-8 attenuated cartilage degeneration, reduced oxidative and ferroptosis-related damage, and showed no apparent systemic toxicity under the tested conditions. This study establishes a composition-engineered MOF nanoplatform that links copper-doped ZIF-8 design with oxidative stress regulation, ferroptosis suppression, and cartilage protection, providing a materials-design strategy for OA microenvironment modulation. Download: Download high-res image (110KB) Download: Download full-size image
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JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
·
2026
·
IF 3.3
Deng Xinyi,Yang Lei,Li Dihua,Wang Yan,Jia Qiang,Li Ning,Meng Zhaowei
Purpose: Anaplastic thyroid carcinoma (ATC) is an exceptionally aggressive malignancy that, despite accounting for only 1%-1.5% of all thyroid cancers, is responsible for over half of thyroid cancer-related deaths. Characterized by limited treatment options and a poor prognosis, ATC presents a critical clinical challenge. In this study, we developed and evaluated an innovative liposomal system (T-AUF-LPs) co-loading Auranofin (AUF) and Timosaponin AIII (TAIII) aimed at inducing ferroptosis in ATC cells. Methods: T-AUF-LPs were prepared via the film-hydration method and their physicochemical properties were characterized. Cellular uptake, anti-proliferative effects, and ferroptosis-related mechanisms—including reactive oxygen species (ROS), iron levels, glutathione (GSH), GPX4, ACSL4, and NCOA4—were assessed in CAL-62 and 8505C ATC cell lines. In vivo antitumor efficacy and biosafety were evaluated using a BALB/c nude mouse xenograft model. Results: T-AUF-LPs showed superior physicochemical properties compared to conventional liposomes, including uniform spherical morphology, reduced particle size, and enhanced encapsulation efficiency. Cellular assays revealed significantly improved uptake of T-AUF-LPs in both ATC cell lines. The formulation inhibited cell proliferation in a dose-dependent manner, an effect effectively reversed by ferrostatin-1, confirming ferroptosis as the primary cell death mechanism. Mechanistic investigations indicated that T-AUF-LPs treatment increased intracellular ROS and iron levels, depleted GSH, and induced upregulation of ACSL4 and NCOA4 along with downregulation of GPX4. In vivo evaluation demonstrated effective tumor growth suppression with an excellent safety profile and no significant organ toxicity. Conclusion: T-AUF-LPs exert potent anti-tumor effects by inducing ferroptosis without causing systemic organ toxicity. They represent a promising therapeutic strategy for ATC, thereby addressing a critical unmet need in the management of this disease.
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APPLIED SPECTROSCOPY
·
2026
·
IF 2.2
Lijuan Huang,Meiqi Liu,Qian Zhang,Ting Yang,Yujia Wu,Dong Yan,Changqi Xu,Dingyi Liu,Jie Yu,Chenghao Chen
This study constructed a dual-substrate colorimetry based on the catalytic activity single-stranded DNA (ssDNA), i.e., 5′-GGT TGG TGT GGT TGG-3′, functionalized gold nanoparticles (AuNPs-ssDNA). By utilizing the peroxidase-mimicking activity of AuNPs and generating differential colorimetric response fingerprints through dual substrates o-phenylenediamine (OPD) and 3-amino-9-ethylcarbazole (AEC), simultaneous discrimination and quantitative detection of Fe2⁺ and Fe3⁺ were achieved. Characterization results showed that the synthesized AuNPs had an average size of about 12 nm. After functionalization, the average diameter of the formed AuNPs-ssDNA complexes increased to 13 nm, and the absorption peak position remained unchanged, indicating that ssDNA modification did not affect their dispersity and morphology. This method, combined with multivariate calibration models, can extract quantitative information from complex response patterns, with a linear detection range for both Fe2⁺ and Fe3⁺ from 0.01 to 100 μM. In practical application validation, the method was successfully used to detect iron ion concentrations in A549 cells treated with the ferroptosis inducer GPX4-IN-7. The results showed high consistency (P ≤ 0.001) with those obtained using a commercial FerroOrange detection kit, demonstrating the potential of this method for practical application in complex biological systems.
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高影响因子
Aggregate
·
2026
·Vol. 7
·期 3
·e70317
·
IF 14.5
Qixuan Wang,Shu Lian,Wenfei Niu,Zhongming Ye,Lejing Hu,Lu Huang,Yanjie Zhang,Xiaodong Xie,Jianping Xie
Gold nanocluster (NC)-induced ferroptosis has emerged as a promising method for malignant tumors. However, the immune clearance and suboptimal reactive oxygen species (ROS) generation efficiency have limited its clinical application. Here, we engineered macrophage-membrane-coated gold nanocluster@nanoflower (CM-NC@NF) nanocomposites to address these challenges. In vitro studies demonstrated that the combination of NC and NF significantly enhanced ROS generation (∼9 times than NC), GSH depletion, and photothermal therapy (PTT) under laser irradiation, therefore promoting apoptosis in both 4T1 and MCF-7 cells. Furthermore, experimental evidence demonstrates that macrophage membrane encapsulation enables CM-NC@NF to evade clearance by immune cells. In the murine breast cancer model, CM-NC@NF exhibited significant tumor accumulation 4 h post-intravenous administration. Subsequent laser irradiation induced robust ROS generation and PTT within the tumor, leading to a tumor inhibition rate 5.7 times higher than that achieved with CM-NC alone. This therapeutic efficacy was further validated in an intra-tumoral injection experiment, showing a tumor inhibition rate 5.4 times higher than that of CM-NC alone. This multimodal strategy synergizes ferroptosis-like therapy with PTT, holding significant therapeutic promise for precision breast cancer treatment.
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Cell Reports Medicine
·
2026
·Vol. 7
·期 3
·
IF 14
Weihao Yang,Chunjie Wang,Chao Yu,Nan Jiang,Bin Yu,Yicheng Ni,Caifang Ni,Liangzhu Feng,Lei Zhang
Transcatheter arterial chemoembolization (TACE) faces limitations in hepatocellular carcinoma (HCC) due to suboptimal drug pharmacokinetics and immunosuppression post-embolization. This study develops iron nanoparticles (FeNPs) with pH-responsive Fenton activity as surfactants for a Lipiodol Pickering emulsion (LPE) to deliver cariporide, targeting tumor acidity. Cariporide inhibits plasma membrane sodium-hydrogen exchangers, reducing intracellular pH to amplify FeNP-induced ferroptosis while suppressing extracellular acidosis by blocking proton extrusion. The cariporide-loaded FeNP-LPE (CFe-LPE) promotes immunogenic cell death and reverses immunosuppressive tumor microenvironments by alleviating acidity. In multiple orthotopic HCC models, CFe-LPE-based transarterial embolization outperforms conventional doxorubicin-Lipiodol TACE, demonstrating that dual modulation of intra/extracellular pH enhances Fenton-catalytic embolic agents by synergistically activating antitumor immunity.
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Advanced Healthcare Materials
·
2026
·
IF 11
Zhiwen Wang,Yue Xie,Jiahui Zhang,Min Yang,Zhiyue Zou,Chun Zhang
Acute kidney injury (AKI) and chronic kidney disease (CKD), despite distinct etiologies, share a common pathological axis characterized by reactive oxygen species (ROS) burst, ferroptosis activation, and sustained inflammation. Targeting this ROS–ferroptosis–inflammation cycle represents a promising therapeutic strategy; however, current nanoplatforms are limited by insufficient responsiveness and limited capacity to regulate shared pathological mechanisms across distinct renal disease models. Here, we develop an engineered ROS-responsive nanozyme by integrating diselenide-bridged organosilica, hyaluronic acid (HA)-modified cerium oxide (CeO 2 ), and a selenium-containing diselenide framework. Under oxidative stress, MON@HA-CeO 2 undergoes ROS-triggered disassembly, coupling HA-CeO 2 -mediated ROS scavenging with selenium-related GPX4 restoration to suppress lipid peroxidation, ferroptosis, and inflammatory amplification. In both glycerol-induced AKI and unilateral ureteral obstruction (UUO)-induced renal fibrosis models, the nanozyme significantly improves renal function and attenuates tissue injury, fibrosis, and inflammation. Overall, this work demonstrates a versatile strategy for targeting a shared pathological axis and provides a promising platform for the treatment of diverse renal diseases.
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Cell Death & Disease
·
2026
·
IF 12.2
Liu Jiaxi,Miao Jiyu,Lv Yang,Fu Bingjie,Ren Xiaomin,Wang Naiqi,Xv Xuezhu,Gao Gongzhizi,Lin Zujie,Zhang Wenxiang,Zhao Bide,Shen Ying,Jia Yachun,Zhao Wanhong,Liu Rui,He Aili
Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled plasma cell proliferation and frequent therapeutic relapse. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic vulnerability in cancer. However, the mechanisms governing ferroptosis resistance in MM remain incompletely understood. Here, we identified thioredoxin (TXN), a central redox regulator, as a ferroptosis suppressor associated with poor prognosis in MM patients. Genetic knockdown or pharmacological inhibition of TXN impaired MM progression and enhanced ferroptosis-associated lipid peroxidation. Mechanistically, TXN suppression induced broad remodeling of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs), particularly phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species enriched in ferroptosis-relevant PUFAs, thereby increasing ferroptosis susceptibility. Rescue experiments using a redox-deficient TXN mutant further demonstrated that the ferroptosis-suppressive function of TXN depends on its redox activity. We further identified interferon regulatory factor 1 (IRF1), which is downregulated in MM, as a transcriptional repressor of TXN. IRF1 depletion increased TXN expression and partially attenuated TXN deficiency-induced lipid peroxidation, supporting the functional relevance of the IRF1-TXN axis in ferroptosis regulation. In addition, bortezomib (BTZ)-resistant MM cells exhibited elevated TXN expression and reduced ferroptosis sensitivity. Targeting TXN restored ferroptotic vulnerability and enhanced BTZ sensitivity in MM cells. Collectively, our findings identify TXN as a critical suppressor of ferroptosis-associated phospholipid remodeling and lipid peroxidation in MM and establish the IRF1-TXN axis as a potential therapeutic target for overcoming ferroptosis resistance and improving MM treatment outcomes.
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高影响因子
RENAL FAILURE
·
2026
·
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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