JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Luyao Xu,Jing Feng,Shihao Xu,Mingli Jin,Xianyue Bai,Hui Zhang,Minghui Zhu,Shengmin Lin,Jiaxing Song,Cuixia Lu
Multimodal targeted combination therapy that harnesses synergistic effects has emerged as a transformative paradigm in cancer therapy, progressively replacing traditional monotherapy. Herein, we report a tumor microenvironment (TME)-responsive multifunctional nanoplatform Cu-Ce6@DHA NPs (CCD NPs), which is self-assembled through the coordination of Cu²⁺, the antitumor drug dihydroartemisinin (DHA), and the photosensitizer chlorin e6 (Ce6). This nanoplatform enables the near-infrared-triggered combination of cuproptosis and ferroptosis for tumor treatment. Upon internalization by tumor cells, these nanoparticles undergo glutathione (GSH)-triggered disintegration, releasing their encapsulated payloads within the TME. The released Ce6 mediates potent photodynamic therapy (PDT) under laser irradiation, and DHA undergoes GSH-dependent activation to generate cytotoxic reactive oxygen species (ROS) and suppresses glutathione peroxidase 4 (GPX4), thereby amplifying ferroptotic cell death. Concurrently, the released copper ions deplete intracellular GSH and further inhibit GPX4, which exacerbates lipid peroxidation and promotes ferroptosis. Notably, the intracellular accumulation of copper ions disrupts mitochondrial metabolism by destabilizing iron-sulfur cluster (Fe-S) proteins and inducing oligomerization of lipoylated lipoylated dihydrolipoamide S-acetyltransferase (DLAT), ultimately triggering cuproptosis. Therefore, our findings establish a novel nanoplatform that simultaneously exploits metabolic vulnerabilities (via cuproptosis), redox imbalances (via ferroptosis), and photodynamic effects, providing a promising multimodal therapeutic strategy for cancer treatment.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2026
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IF 5.2
Shuo Liu,Hong Zhang,Mariano Romero,Dominique Mombrú,Alvaro W. Mombrú,JitKang Lim,Ruirui Zhao,Chunzhao Liu
Iron-based multifunctional self-assembly nanoparticles was prepared. • Enhanced ROS generation and depleted GSH to amplify oxidative damage. • Suppressed tumor cell migration and induced immunogenic cell death. • Offred a promising cocktail strategy for effective prostate cancer treatment. Ferroptosis, an iron-dependent programmed cell death pathway, has emerged as a promising therapeutic strategy that is distinct from apoptosis. In this study, we designed and fabricated iron-based multifunctional self-assembly nanoparticles (SCCuFe NPs) consisting of ferroptosis promoter Fe 3 O 4 -COOH, ferroptosis inducer sorafenib, photosensitizer chlorin e6 (Ce6), and metal ion copper ions (Cu 2+ ) for synergetic chemodynamic-ferroptosis-photodynamic therapy of prostate cancer. SCCuFe NPs exhibited excellent biocompatibility, were readily internalized by tumor cells, and enhanced cytotoxicity against PC3 cells. These nanoparticles catalyzed the decomposition of hydrogen peroxide into hydroxyl radicals for chemodynamic therapy (CDT), generated singlet oxygen under laser irradiation for photodynamic therapy (PDT), and induced ferroptosis by downregulation of GPX4 expression. In addition, SCCuFe NPs depleted intracellular glutathione and amplified ROS production, thereby increasing lipid peroxide accumulation and reinforcing ferroptosis. Moreover, in vitro studies demonstrated that SCCuFe NPs under laser irradiation significantly inhibited PC3 cell migration and induced immunogenic cell death by promoting the extracellular release of high-mobility group box-1 (HMGB1). Collectively, these iron-based, multifunctional, self-assembled nanoparticles represent a promising cocktail therapy strategy by simultaneously integrating ferroptosis, CDT, and PDT for the effective management of prostate cancer. Download: Download high-res image (517KB) Download: Download full-size image
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
·
IF 15
Wang Huan-Hui,Nan Long-Yi,Zheng Yan,Guo Jianpeng
Sonodynamic therapy (SDT) offers deep tissue penetration and noninvasive tumor treatment, yet its efficacy remains limited by inadequate reactive oxygen species (ROS) generation and an immunosuppressive tumor microenvironment (TME). In this work, we developed a porphyrin-based bimetallic nanoplatform by integrating Fe and Mn centers within a structurally ordered metal-organic framework (MOF), followed by surface modification with the tumor-homing peptide CRGDK to achieve active targeting. The rationally engineered Mn-Fe(TCPP) MOF exhibits a spatially confined configuration that minimizes π-π aggregation of porphyrins enhancing ROS production under ultrasound (US). Meanwhile, Fe 3+ and Mn 2+ are released in the mildly acidic TME. The Fe 3+ catalyzes Fenton-like reactions to generate abundant •OH radicals, leading to glutathione (GSH) depletion, glutathione peroxidase-4 (GPX4) inhibition, and triggers ferroptosis. Simultaneously, Mn 2+ and ROS inflict mitochondrial damage and cause cytosolic double-stranded DNA (dsDNA) leakage, thereby activating the cGAS-STING signaling pathway and amplifying type I interferon (IFN-I) responses. This dual immunometabolic modulation induces immunogenic cell death (ICD), promotes dendritic cells (DCs) maturation, and strengthens adaptive antitumor immunity. Overall, this study presents a concise strategy coupling ferroptosis induction with innate-immune activation through a porphyrinic bimetallic MOF, offering a promising direction for SDT-based immunotherapy against hard-to-treat tumors. Graphical The alternative text for this image may have been generated using AI.
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BRITISH JOURNAL OF PHARMACOLOGY
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2026
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IF 7.5
Chang Liu,Zhuoqun Wang,Linxin Zhang,Di Yang,Zhihong Zhang,Xiaoli Cui,Ali H. Eid,Mengyang Wang
Background and Purpose Fangchinoline (FAN), a bioactive bisbenzylisoquinoline alkaloid from Stephania tetrandra , shows protective potential against angiotensin II (Ang II)-induced hypertensive heart failure (HF), particularly involving mitophagy and ferroptosis, remain unclear. We investigated the effects of FAN on Ang II-induced cardiac remodelling and HF. Experimental Approach A hypertensive heart failure model was established in C57BL/6 mice via 4-week Ang II infusion. FAN was administered during the final 2 weeks. Cardiac function was assessed by echocardiography and pathological remodelling was evaluated by histological staining. RNA sequencing of cardiac tissue was performed to investigate the mechanism of anti-heart failure action of FAN. The potential binding proteins of FAN were verified by molecular docking, drug affinity response target stability (DARTS), cellular thermal shift assay (CETSA) and surface plasmon resonance assay (SPR). In vitro , neonatal rat ventricular myocytes (NRVMs) were used to investigate the effects of FAN on cellular hypertrophy, mitophagy and ferroptosis. Key Results In vivo , FAN treatment significantly ameliorated cardiac hypertrophy, dysfunction and fibrosis. These protective effects were independent of blood pressure-lowering actions. Mechanistically, FAN activates PGC-1α to enhance mitophagy and suppress STAT6-PPARγ signalling, thereby inhibiting ferroptosis and restoring redox homeostasis. In vitro , FAN reduced Ang II-induced NRVM hypertrophy, ROS production and mitochondrial membrane potential depolarisation, and confirmed the modulation of mitophagy and ferroptosis markers. Conclusions and Implications We demonstrate that FAN alleviates Ang II-induced HF through a mechanism involving the activation of PGC-1α-mediated mitophagy and regulation of the STAT6-PPARγ pathway, ultimately suppressing cardiomyocyte ferroptosis. These results offer new perspectives for HF treatment. Graphical FAN mitigates HF by engaging PGC-1α-mediated mitophagy and STAT6-PPARγ to counteract ferroptosis.
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Frontiers in Immunology
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2026
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IF 7
Xiaokun Shen,Haitao Cao,Fujie Li,Wenya Wang,Xingshu Qi,Yarui Zhou,Bo Li,Qingjie Fan,Tao Yang,Shinan Li
Liver fibrosis is a major global health challenge, and it is an independent risk factor for the development of hepatocellular carcinoma (HCC). Several methods have been explored to improve liver fibrosis progression, but effective preventive and therapeutic strategies remain limited. Natural killer (NK) cells can limit the activation of hepatic stellate cells (HSCs), but they have exhibited impaired antifibrotic properties in liver fibrosis, and the underlying mechanisms are not well understood. In this study, we found that CD36 was markedly upregulated in NK cells from mice with liver fibrosis. The CD36 expression was negatively correlated with activation markers of NK cells. The CD36- NK cells exhibited elevated cytotoxic cytokine production and enhanced antifibrotic activity against HSCs. The adoptive transfer of CD36- NK cells alleviated liver fibrosis progression. Mechanistically, CD36 induced reactive oxygen species (ROS) and lipid peroxidation. These consequently triggered ferroptosis in NK cells. The blockage of CD36 or inhibition of ferroptosis in NK cells effectively restored their antifibrotic properties against HSCs. In summary, our findings demonstrated that the antifibrotic properties of NK cells were regulated by CD36. These results provide evidence that targeting CD36 could restore NK cell function for liver fibrosis immunotherapy.
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NEUROPHARMACOLOGY
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2026
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IF 4.7
Ruinan Ni,Shulin Bi,Zhihong Cheng,Shangqi Ni,Yang Guo,Yu Xiang,Bin Peng
Neuropathic pain (NP) remains a clinical challenge due to the limited efficacy and significant side effects of current treatments, highlighting the need for a deeper understanding of its pathogenesis. While dysfunction of GABAergic inhibitory neurons in the spinal dorsal horn is a known key driver of central sensitization, the mechanisms precipitating this neuronal injury remain obscure. In this study, using a spinal nerve ligation (SNL) model, we aimed to investigate whether the chemokine CXCL10 drives NP progression by promoting ferroptosis, a process that is associated with and ultimately leads to the loss of GABAergic neurons. We observed that mechanical hypersensitivity in post-SNL rats coincided with progressive spinal ferroptosis, characterized by iron accumulation, lipid peroxidation, and suppression of the GPX4/xCT system. Notably, CXCL10 expression mirrored the trajectory of ferroptosis. Interventional studies established CXCL10 as an upstream initiator, rather than a consequence, of the ferroptotic process. Mechanistically, we demonstrated that CXCL10 activates STAT3 through the CXCR3 receptor; activated STAT3 then acts as a transcriptional repressor to downregulate the cystine transporter xCT, thereby triggering ferroptosis. This molecular cascade resulted in a significant loss of spinal GABAergic neurons, which could be partially reversed by CXCL10 inhibition. Collectively, our findings uncover a novel mechanism of NP maintenance, wherein the CXCL10/CXCR3/STAT3 axis disrupts the spinal excitation-inhibition balance by promoting ferroptosis-mediated loss of inhibitory neurons. These results offer a fresh perspective on NP pathology and identify this signaling axis as a promising therapeutic target.
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HISTOCHEMISTRY AND CELL BIOLOGY
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2026
·Vol. 164
·期 1
·19
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IF 2.9
Tang Yingqi,Wang Siyao,Wang Yu,Zhang Tianyuan,Liu Yu,Di Yunhua
Renal tubular damage and interstitial fibrosis are highly linked to diabetic kidney disease (DKD) progression. Ferroptosis in renal tubular epithelial cells has emerged as one of the key mechanisms of DKD. Spermidine/spermine N1-acetyltransferase 1 (SAT1) knockdown has been found to alleviate repetitive low-dose cisplatin-induced kidney damage and fibrosis, and importantly, SAT1 silencing represses cellular sensitivity to ferroptosis. However, the effect of SAT1 on DKD-associated ferroptosis and its potential mechanism remain understood. In this study, we constructed a high-fat diet/streptozotocin-induced DKD mouse model and a high glucose (HG)-injured HK-2 cell model with the aim of verifying whether SAT1 silencing attenuates DKD tubular damage by regulating ferroptosis. We found that SAT1 was upregulated in DKD mouse kidneys and HG-treated HK-2 cells. Significant tubular damage, fibrosis, ferroptosis, and oxidative stress were observed in DKD mouse kidneys. In an in vitro loss-of-function assay, SAT1 silencing suppressed HG-induced HK-2 cytotoxicity, extracellular matrix (ECM) synthesis, and inflammation. Additionally, SAT1 silencing decreased HG-activated MDA and 4-HNE production, while restoring GSH levels. SAT1 silencing also abrogated HG-activated ferroptosis in HK-2 cells, as evidenced by a reduction in iron overload, inhibition of lipid peroxidation, and upregulation of ferroptosis-related protein (SLC7A11, GPX4, and TFR1) expression. Mechanistically, SAT1 silencing facilitated nuclear translocation and expression of NRF2. Impairment of NRF2 function abrogated the inhibitory effects of SAT1 silencing on HG-stimulated HK-2 cytotoxicity, ferroptosis, and ECM accumulation. Overall, the SAT1/NRF2 axis is a critical regulator of tubular damage in DKD, and suppression of SAT1 may be an underlying target for DKD treatment.
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FREE RADICAL BIOLOGY AND MEDICINE
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2026
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IF 8
Shiyi Zhang,Tongpeng Yue,Peixuan Jin,Xinyi Zhang,Qidong Huo,Wenxuan Li,Chen Tian,Hui Dong,Yinping Dong,Yu Zhao,Deguan Li
Radiation-induced intestinal injury (RIII) is a serious and common complication of radiotherapy, and there are currently no effective therapeutic strategies. This study investigates the protective role of 4-octyl itaconate (4-OI), a cell-permeable itaconate derivative, against RIII. In vitro , 4-OI pretreatment enhanced the viability of irradiated intestinal epithelial cells, reduced reactive oxygen species (ROS) accumulation, and alleviated DNA damage. In a murine model of total body irradiation, 4-OI administration mitigated intestinal structural disruption, promoted crypt stem cell regeneration, and suppressed epithelial apoptosis. Mechanistically, 4-OI exerted its cytoprotective effects by modulating the SLC7A11/GPX4 axis to inhibit ferroptosis and enhancing glutathione biosynthesis. Furthermore, 16S rRNA sequencing revealed that 4-OI treatment recalibrated radiation-induced gut microbiota dysbiosis, suggesting an additional microbiome-mediated protective pathway. To our knowledge, the results represent the first demonstration of 4-OI's protective effects in RIII pathogenesis, positioning it as a novel therapeutic candidate for clinical radioprotection through dual mechanism targeting.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2026
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IF 8.7
Fei Chen,Dong Zhang,Xiaonan Ding,Yingjie Duan,Junxia Du,Chenwen Song,Qiuxia Han,Qinqin Ren,Xiaolin Zhao,Qinglin Li,Zhiyuan Gao,Mingwei Tian,Ke Tan,Hanyu Zhu
Heatstroke-induced acute kidney injury (HS-AKI) is a serious clinical complication, with ferroptosis implicated in its pathogenesis. While heat shock factor 1 (HSF1) is a known regulator of ferroptosis, its role in HS-AKI remains unclear. Here, we demonstrated that heatstroke triggered ferroptosis-associated renal damage in mice, characterized by elevated serum creatinine, blood urea nitrogen, and tissue iron deposition, alongside transcriptomic signatures of ferroptosis and HSF1 pathway activation. Notably, HSF1 expression was transiently activated by heat stress, and simultaneously promoted the expression of heat shock proteins (HSPs), but decreased in the late phase of heat shock. Knockdown of HSF1 in renal tubular cells exacerbated HS-induced ferroptotic death. Conversely, renal-specific overexpression of HSF1 rescued heatstroke-caused deleterious phenotype in mice. Importantly, pharmacological activation of HSF1 by HSF1A attenuated oxidative stress, rectified iron dyshomeostasis, inhibited lipid peroxidation, and conferred significant protection against HS-AKI. These results identify HSF1 activation as an endogenous adaptive response that limits ferroptosis during heatstroke, positioning HSF1A as a promising therapeutic candidate for HS-AKI.
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MOLECULES
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2026
·Vol. 31
·期 15
·2559
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IF 5.1
Yiyao Gong,Jie Zhang,Tingting Wang,Xiang Li,Hao Wang,Li Ren
Chronic exposure to lead (Pb) represents a persistent environmental hazard that can impair hippocampal integrity and cognitive function, while effective protective strategies remain limited. Ginsenoside Rg1 is an important bioactive constituent derived fromPanax ginsengand has been reported to possess antioxidant and neuroprotective activities; however, its involvement in Pb-triggered ferroptosis-associated neuronal damage remains unclear. In the present study, a male C57BL/6J mouse model of subchronic lead acetate exposure and a lead-exposed HT22 cell model were established. Behavioral and histopathological changes were assessed, followed by analysis of inflammatory responses, oxidative stress, ferroptosis-related alterations, and Nrf2-associated signaling. Rg1 improved cognitive performance and attenuated hippocampal neuronal loss, neuroinflammatory activation, oxidative injury, and ferroptosis-related alterations, including ferrous ion accumulation and mitochondrial damage. Consistently, Rg1 restored SLC7A11/xCT and GPX4 expression and enhanced Nrf2-associated antioxidant signaling, whereas the Nrf2 inhibitor ML385 weakened the Rg1-induced increases in nuclear Nrf2, NQO1, and GPX4. Collectively, these findings indicate that Rg1 alleviates lead-induced neurotoxicity and support the involvement of Nrf2 signaling in the regulation of oxidative stress and ferroptosis-related injury. These findings provide experimental evidence supporting further preclinical investigation of Rg1 and its Nrf2-associated neuroprotective mechanisms in Pb-induced neuronal injury.
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Frontiers in Bioscience-Landmark
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2026
·Vol. 31
·期 7
·
IF 4.1
Zhenxin Huo,Ding Li,Yuxuan Kuang,Baoshan Xu
Background: Intervertebral disc degeneration (IDD) is a major pathological contributor to low back pain, and its progression is closely associated with oxidative stress and cell death. Ferroptosis is a form of programmed cell death characterized by iron-dependent lipid peroxidation, which has recently been confirmed to participate in IDD progression. Microsomal glutathione S-transferase 1 (MGST1) plays an important role in glutathione metabolism and cellular antioxidant defense, but its function in IDD remains unclear. This study aimed to investigate the expression profile of MGST1 in IDD and to elucidate its molecular mechanism in delaying degeneration by regulating ferroptosis. Methods: Differentially expressed ferroptosis-related genes associated with intervertebral disc degeneration were screened through bioinformatics analysis. MGST1 expression changes were validated using a needle puncture-induced rat IDD model and a degenerated nucleus pulposus (NP) cell model. MGST1 knockdown and overexpression strategies were employed to evaluate its effects on the extracellular matrix metabolism, apoptosis, and senescence of nucleus pulposus cells. Further examinations of ferroptosis-related indicators were conducted, including levels of lipid peroxidation, reactive oxygen species generation, intracellular Fe2+ content, and changes in mitochondrial membrane potential. For in vivo experiments, the therapeutic effect of MGST1 overexpression was assessed by intradiscal injection of an MGST1-overexpressing lentivirus into the rat intervertebral disc degeneration model. Results: Bioinformatics analysis indicated that MGST1 is a key candidate gene in IDD. MGST1 expression was consistently upregulated with increasing degeneration severity in rat disc tissues and degenerated NP cells. Knockdown of MGST1 significantly promoted extracellular matrix degradation and increased apoptosis and senescence levels in NP cells, while MGST1 overexpression markedly improved these changes. Mechanistic studies revealed that MGST1 deficiency significantly enhanced ferroptosis characteristics in NP cells, including accumulation of lipid peroxides and ROS, increased Fe2+ content, and decreased mitochondrial membrane potential. In vivo experiments demonstrated that MGST1 overexpression significantly alleviated the degree of IDD in rats. Conclusion: MGST1 exhibits compensatory upregulation during the progression of intervertebral disc degeneration and delays its progression by inhibiting ferroptosis in nucleus pulposus cells. This study reveals a novel mechanism by which MGST1 regulates ferroptosis in IDD and provides a potential molecular target for the prevention and treatment of IDD.
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Advanced Healthcare Materials
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2026
·
IF 11
Shuang Liu,Hewen Li,Yuhang Ding,Dengyi Duan,Lin Cao,Kangkang Liu,Wenyi Zhang,Shifeng Cheng,Yiming Li,Yunfei Guo,Xiang Qi,Jianmin Li,Xuening Zhang,Jing Peng,Gang Han,Yang Zhao
Ferroptosis is triggered by iron-dependent lipid peroxidation, which shows great potential in tumor therapy. However, its biomedical applications are constrained by suboptimal therapeutic efficacy, leakage of metal ions from inducing agents, and the absence of noninvasive evaluation methods. In this study, we aimed to develop a self-reducing nano-theranostic agent (Fe@AP-SAS/RGD, FASR) for tumor-targeted ferroptosis therapy and conducted real-time magnetic resonance imaging(MRI) to monitor ferroptosis by encapsulating iron oxide particles in natural apple pectin (AP). In a weakly acidic tumor microenvironment, the strong reducing ability of AP accelerated the transformation of Fe 3+ within FASR into highly active Fe 2+ . Subsequently, the concentration of Fe 2+ increased and boosted the antitumor effect of ferroptosis. Notably, MRI of prostate cancer mouse models after intravenous injection of FASR NPs at varying doses revealed that the T 2 value decreased at the tumor sites and exhibited a linear correlation with the changes in ferroptosis hallmark markers, tumor weight, and volume after treatment. These findings demonstrate the capacity of T 2 mapping to quantitatively evaluate ferroptosis efficacy. This study not only introduced a tumor-targeted and self-reducing strategy to amplify ferroptosis but also pioneered a novel pathway for noninvasive imaging and monitoring of ferroptosis treatment processes within live tumors.
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