JOURNAL OF CONTROLLED RELEASE
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2026
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IF 12.4
Dongjing Wang,Xiaonan Li,Kunpeng Wei,Suyan Wang,Wen Zuo,Ze Xu,Chen Li,Hui Wang,Xueyan Zhou,Yanzhuo Zhang
Acute kidney injury (AKI) is a prevalent clinical syndrome associated with high morbidity, mortality, and a heavy medical burden. Oxidative stress, inflammation, and ferroptosis are key drivers of AKI, yet current pharmacotherapies are limited by suboptimal efficacy and systemic side effects. An efficient and precise kidney-targeted delivery system that co-delivers complementary therapeutics could overcome these challenges. Herein, we report a platelet membrane–coated, reactive oxygen species (ROS)-responsive nanozyme (BAPCs@PM) for synergistic AKI therapy. Ultrasmall CeO 2 nanodots (∼3 nm) were in situ mineralized on the outer layer of polydopamine cores, and hydrophobic baicalein was loaded into the mesoporous interior, yielding a stable and well-dispersed multifunctional composite nanozyme. Platelet membrane cloaking conferred renal targeting, immune evasion, and prolonged circulation. BAPCs@PM enabled ROS-triggered release of CeO 2 nanodots and sustained baicalein delivery at injured sites, amplifying local antioxidant, anti-inflammatory, and anti-ferroptotic activity. In a cisplatin-induced AKI model, BAPCs@PM markedly suppressed kidney injury molecule-1 upregulation, inhibited cleaved caspase-3 activation and apoptosis, enhanced mitochondrial protection, modulated macrophage polarization, reduced proinflammatory cytokine production, regulated iron homeostasis, restored glutathione peroxidase 4 expression, attenuated ferroptosis and lipid peroxidation, and ultimately improved renal function. Owing to their ultrasmall size, the ceria nanodots achieved efficient renal accumulation and rapid clearance with minimal systemic toxicity. This study provides an innovative biomimetic and responsive therapeutic strategy for AKI by combining ultrasmall nanozymes, natural bioactive molecules, and biomimetic membrane engineering.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2026
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IF 8.7
Yuqiong Guo,Ziyi Xiao,Fangjing Wang,Guihui Zhu,Jian Sun,Yang Liu
An injectable hyaluronic acid-based hydrogel delivery platform was fabricated. • It possessed targeting and responsive delivery performance with reduced toxicity. • Ferrocenediboronic acid served as both crosslinker and ferroptosis inducer. • It achieved synergistic chemotherapy and ferroptosis therapy for breast cancer. Polysaccharide hydrogels have significant research significance and application value in fields such as drug delivery and tumor treatment. Herein, a multifunctional injectable polysaccharide hydrogel platform, BFc-PVA/OHA@DOX (BPOD), was designed for the local controllable and long-lasting delivery of doxorubicin (DOX), thereby achieving synergistic chemotherapy and ferroptosis therapy against breast cancer. It was fabricated by physical blending ferrocenediboronic acid (BFc), polyvinyl alcohol (PVA), and oxidized hyaluronic acid (OHA) conjugated with DOX through Schiff base bonds, through the crosslinking of borate ester bonds and hydrogen bonds. It displayed favorable stimulus responsiveness, injectability, self-healing capacity, biodegradability, and biocompatibility, while maintaining the intrinsic Fenton reaction activity of BFc. Within the tumor microenvironment, BPOD enabled the sustained responsive release of DOX and BFc for no less than 10 days. DOX accumulated in tumors through OHA-mediated cellular internalization and induced apoptosis via DNA damage. Meanwhile, BFc generated reactive oxygen species (ROS) and decreased glutathione (GSH) level, thus effectively triggering ferroptosis. Both in vitro and in vivo results demonstrated that BPOD held remarkable anti-breast-cancer activity with reduced systemic toxicity. This work establishes an injectable polysaccharide hydrogel local delivery platform with enhanced cellular internalization, multi-responsive behavior, and synergistic enhancement effects, providing novel technical approaches and strategies for addressing key challenges in clinical treatment of breast cancer.
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BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Tong Sha,Kun Jiao,Jianing Li,Ye Zheng,Linbin Wang,Zhi Cui
Oral squamous cell carcinoma (OSCC) is an aggressive head and neck malignancy. Lysine acetyltransferase 2B (KAT2B) exerts tumor-suppressive functions in various cancers, yet its function in OSCC remains unclear. Through integrative analysis of five public transcriptomic datasets with validation in clinical tissues and cell lines, we identified a consistent reduction of KAT2B expression in OSCC. Functional assays demonstrated that KAT2B overexpression inhibited OSCC cell proliferation, tumorsphere formation, stemness marker expression, and in vivo tumor growth, whereas KAT2B silencing produced opposite effects. Furthermore, KAT2B overexpression enhanced RSL-3-induced ferroptosis, evidenced by increased Fe 2+ accumulation, elevated lipid reactive oxygen species (ROS) levels, aggravated mitochondrial damage, and reduced GPX4 protein; conversely, KAT2B knockdown conferred ferroptosis resistance. Mechanistically, integrating mRNA sequencing with the FerrDb database identified glutathione S-transferase zeta 1 (GSTZ1) (log 2 FC = 1.44, p < 0.001) as a key downstream target of KAT2B in ferroptosis regulation. ChIP-qPCR confirmed that KAT2B transcriptionally activates GSTZ1 by enhancing histone H3 lysine 9 acetylation (H3K9ac) enrichment at its promoter. Rescue assays further confirmed that depletion of GSTZ1 counteracted the effects of KAT2B overexpression on OSCC cell proliferation and ferroptosis. Collectively, we find that KAT2B transcriptionally activates GSTZ1 in a H3K9ac-dependent manner, which in turn inhibits GPX4 expression, thereby suppressing OSCC proliferation and stemness while enhancing ferroptosis sensitivity. This defines the KAT2B-GSTZ1 axis as a novel tumor-suppressive mechanism and an emerging therapeutic target for OSCC
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CHINESE CHEMICAL LETTERS
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2026
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IF 9.5
Meng-Meng Zhang,Yu-Han Zheng,Hao-Bin Che,Qiang Dai,Lei Xing,Xian Wu Cheng,Tian-Jiao Zhou,Hu-Lin Jiang
Ferroptosis, driven by lethal lipid peroxidation (LPO), represents a promising therapeutic strategy for triple-negative breast cancer (TNBC). However, its efficacy is severely compromised by spatially distinct cellular antioxidant defense systems, particularly the cytosolic glutathione (GSH) and the membrane-bound coenzyme Q (CoQ). To dismantle these parallel LPO defenses from the aqueous interface to the hydrophobic bilayer, we developed a coordinated strategy utilizing an albumin-based nanoplatform (H-FS NPs) for the co-delivery of sorafenib and fluvastatin. Mechanistically, sorafenib suppresses cytoplasm GSH levels by inhibiting the xCT subunit, thereby dismantling the GSH-glutathione peroxidase 4 (GPX4) pathway. Concurrently, fluvastatin inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) activity in the mevalonate pathway, thereby reducing CoQ synthesis and disrupting the intrinsic anti-peroxidation defense within the lipid bilayer. Synchronously dismantling these compartmentalized defense systems ignites a self-amplifying LPO cascade, resulting in potent ferroptosis and profound tumor suppression in TNBC models. This work highlights that dismantling spatially compartmentalized antioxidant barriers is a powerful therapeutic strategy for TNBC treatment.
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Materials Today Bio
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2026
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IF 11
Xinnan Xu,Keyi Chen,Tao Ge,Ming Deng,Li Xu,Kaiqi Jin,Xuyu Gu
Lung cancer chemotherapy is often limited by insufficient tumor-selective drug delivery, premature leakage, and the difficulty of coordinating multiple therapeutic mechanisms in an optimal temporal sequence. Here, we developed a sequentially programmed Fe 2 O 3 hollow multishelled nanoplatform, Fe 2 O 3 -HoMS-(SS-ART)-Oxa@CaP, to achieve shell-selective loading and microenvironment-responsive release for chemo-ferroptotic therapy. In this design, oxaliplatin (Oxa) was preferentially positioned in the outer shell/pore region for relatively early release, whereas a reduction-responsive disulfide-linked artesunate prodrug (SS-ART) was confined within the inner structure for delayed glutathione-triggered activation, and an ultrathin CaP layer served as an acid-responsive gatekeeper. This structural organization enabled a programmed release tendency that supports early chemotherapeutic priming followed by redox amplification. Mechanistically, Fe 2 O 3 -HoMS-(SS-ART)-Oxa@CaP increased intracellular Fe 2+ availability and ROS accumulation, depleted GSH, and suppressed GPX4, with results consistent with enhanced ferroptosis-related tumor cell damage. The nanoformulation also induced CRT exposure and HMGB1 redistribution, suggesting immunogenic cell death-associated molecular changes. Functionally, it significantly inhibited A549 cell proliferation, migration, and invasion compared with free drugs and their free combination. In vivo, the nanoplatform achieved improved tumor suppression, increased TUNEL positivity, reduced GPX4 expression, prolonged survival, and was associated with a shift in tumor-associated macrophages toward a more CD86-positive/M1-like and less CD206-positive/M2-like phenotype, with no obvious systemic toxicity under the tested conditions. Together, these findings support this Fe 2 O 3 -based hollow multishelled nanoplatform as a proof-of-concept strategy for programmed chemo-ferroptotic therapy in lung cancer, while also suggesting macrophage-related innate immune changes in vivo.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2026
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IF 9.6
Yuan Fang,Yan Zhang,Hanhan Zhu,Wenxuan Ye,Zhiting Sun,Dianmin Xia,Dekun Cen,Zhisheng Ji,Jing Lin,Jianfu Zhao,Siming Yu
Sulfur dioxide (SO 2 ) has been recognized as the fourth gasotransmitter and holds great promise for antibacterial infection therapy. However, near-infrared (NIR) laser-triggered SO 2 -releasing nanoplatforms remain underdeveloped. Herein, a raspberry-like mesoporous Fe single atom nanozyme (Fe mSAz) with NIR-II laser-reinforced peroxidase (POD)-like activity was synthesized to construct a smart SO 2 -controlled release platform. To this end, the SO 2 donor 2,4-dinitrobenzenesulfonyl chloride (DN) was first loaded into the pores of Fe mSAz with the aid of a phase change material (PCM), followed by surface functionalization with a macrophage membrane (M), yielding a biomimetic SO 2 -releasing nanozyme denoted Fe mSAz@DN@M. Upon 1064 nm laser irradiation, the photothermal effect of Fe mSAz@DN@M first induced melting of the PCM to release DN, which subsequently triggered a burst of SO 2 generation. In the meantime, 1064 nm laser irradiation enhanced the POD-like activity of Fe mSAz by generating a substantial amount of hydroxyl radical (ꞏOH). As a result, Fe mSAz@DN@M exhibited robust antibacterial efficacy through a synergistic SO 2 /ꞏOH effect. Mechanistic studies revealed that SO 2 and ꞏOH synergistically suppressed bacterial activity by amplifying bacterial ferroptosis-like death. Furthermore, due to macrophage membrane functionalization, Fe mSAz@DN@M achieved highly effective targeting of subcutaneous tissues infected with Staphylococcus aureus ( S. aureus ) in mice. Consequently, Fe mSAz@DN@M also demonstrated excellent in vivo antibacterial infection efficacy through the synergistic SO 2 and ꞏOH effect, which not only eradicated the infectious bacteria but also subsequently induced repolarization of anti-inflammatory M2 macrophages to promote wound healing. A biomimetic SO 2 -releasing Fe single atom nanozyme (Fe mSAz@DN@M) was reported. NIR-II laser irradiation controls the simultaneous release of both ꞏOH and SO 2 , which synergistically boosted the antibacterial infection efficacy of the nanozyme by amplifying bacterial ferroptosis-like death. Download: Download high-res image (163KB) Download: Download full-size image
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ENVIRONMENT INTERNATIONAL
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2026
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IF 10.2
Fan Yu,Shihao Luo,Zhengrong Zhou,Feixia Chen,Jiawei Ying,Qiufang Wu,Yize Wu,Shihua Chen,Xinxin Yao,Feiqin Xie,Wenhui Xu,Ke Xu,Renyi Peng
Cypermethrin (CY), a pyrethroid insecticide, accumulated in aquatic environments and exertd toxic effects on aquatic organisms, impairing their development, nervous system, and immune function. Polystyrene nanoparticles (PS-NPs) readily adsorbed organic contaminants like CY, forming complex pollution systems that resulted in synergistic toxicities. However, the mechanisms behind their hepatotoxicity remained unclear. In this study, both in vivo and in vitro experiments demonstrated that co-exposure to PS-NPs and CY significantly induced liver injury and steatosis in zebrafish larvae, while activating the key lipid synthesis regulator sterol regulatory element-binding protein 1 (SREBP1) in Hep G2 cells. This process displayed typical features of ferroptosis, including oxidative stress, mitochondrial damage, iron dysregulation, and suppression of the antioxidant enzyme glutathione peroxidase 4 (GPX4). Correlation analysis showed a close association between ferroptosis and steatosis. Physiological and genetic verification revealed that Erastin aggravated lipid accumulation by inhibiting GPX4 expression, activating the SREBP1/SCD1 lipid synthesis pathway. Conversely, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, alleviated oxidative stress, iron overload, and lipid accumulation, while GPX4 overexpression reversed SREBP1/SCD1 activation and improved lipid accumulation, peroxidation, and ferroptosis. This study revealed a novel mechanism by which PS-NPs and CY co-exposure induced ferroptosis-mediated hepatic steatosis through GPX4. These findings provided new insights into the hepatometabolic toxicity of complex pollutants and identified potential targets for preventing related liver diseases.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.7
Wang Haijing,Gao Jie,Bai Xuefei,Liu Xiaofeng,Qu Shurong,Gao Yugang,Zhao Yan,Teng Hongbo
Age-related hearing loss (ARHL) is a pervasive sensorineural
deficit
lacking effective pharmacological interventions. Although Eleutherococcus senticosus fruit extracts exhibit
otoprotective potential, their precise bioactive constituents and
underlying molecular mechanisms remain elusive. Using network pharmacology
and transcriptomic analysis as hypothesis-generating tools, followed
by experimental validation, this study identifies chiisanoside (CSS)
as a key bioactive compound mitigating d -galactose-induced
cellular senescence and auditory impairment, with an optimal effective
dose of 25 μM in vitro (HEI-OC1 cells) and 50 mg/kg/day in vivo
(oral gavage in C57BL/6 mice). Mechanistically, the in vitro and in
vivo models demonstrate that CSS suppresses age-related auditory decline
primarily by targeting the SESN2/AMPK signaling axis. Specifically,
CSS upregulates SESN2 to activate AMPK, which not only enhances autophagy
via the mTOR/ULK1 pathway but also concurrently inhibits the HIF-1α/TFRC/FTH1
cascade. These findings provide mechanistic insights supporting the
potential of CSS as a therapeutic candidate in ARHL.
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Cell Death & Disease
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2026
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IF 12.2
Liu Yanyan,Guan Chenxi,Xu Linlin,Yang Jianhua,Wang Jinglei,Yang Si,Chen Jiaxiang
Impaired Leydig cell function leads to low testosterone levels, which is associated with male reproductive developmental defects and functional disorders. Exposure to di(2-ethylhexyl) phthalate (DEHP), an endocrine-disrupting chemical, can cause damage to Leydig cells, yet the underlying mechanism remains unclear. In this study, we found that DEHP exposure decreased serum testosterone levels and triggered ferroptosis of mouse Leydig cells by inhibiting GPX4 expression. Subsequently, mono(2-ethylhexyl) phthalate (MEHP), the primary active metabolite of DEHP, was shown to suppress the transcription of Gpx4 gene in TM3 cells by downregulation of HOXA3, which bound to the −264 to −258 region (RE3) of Gpx4 gene promoter. Concurrently, MEHP promoted HSC70 to recognize and degradate GPX4 protein via chaperone-mediated autophagy (CMA). Furthermore, both overexpression of HOXA3 and inhibition of CMA significantly abrogated MEHP-induced ferroptosis of TM3 cells through upregulating the expression of GPX4. Ultimately, tannic acid (TA), a natural polyphenol, was identified to increase the expression of GPX4 and inhibit MEHP-induced ferroptosis of TM3 cells, thereby alleviating DEHP-caused testicular damage in mice through the upregulation of HOXA3 and inhibition of CMA.
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ANTIOXIDANTS & REDOX SIGNALING
·
2025
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IF 6.1
Xian-Dong Li,Yue-Xin Ning,Yi-Feng Pei,Jing-Yuan Niu,Jian Luo,Yi-Na Zhang,Zi-Ai Zhao,Xiao-Wen Hou,Qian-Kun Zhao,Tian-Ce Xu,Hui-Sheng Chen
Aims: Cathodal transcranial direct current stimulation (C-tDCS), a noninvasive physical therapy, has potential neuroprotective effects in acute ischemic stroke. However, the rational timing of its application and the underlying mechanisms remain inadequately understood. This study aims to investigate its neuroprotective effects and the involved mechanisms.Results: Our in vivo results indicated that C-tDCS applied during the reperfusion phase but not during the ischemic phase significantly improved neurological outcomes, reduced infarct volume, and mitigated histopathological damage in middle cerebral artery occlusion/reperfusion rats. C-tDCS during the reperfusion phase suppressed ferroptosis, activated nuclear factor erythroid 2-related factor 2 (Nrf2), and inhibited mitophagy. In vitro, the ferroptosis inducer RSL3 negated the protective effects of cathodal direct current stimulation on HT22 neuronal cells subjected to oxygen-glucose deprivation/reoxygenation injury. Furthermore, the Nrf2 inhibitor ML385 and the mitophagy activator FCCP reversed the inhibitory effects of C-tDCS on ferroptosis, with FCCP also affecting Nrf2 activation by C-tDCS.Innovation and Conclusions: These results demonstrate that C-tDCS during reperfusion attenuates cerebral ischemia-reperfusion injury by coordinating mitophagy inhibition and Nrf2 activation to counteract ferroptosis, which provides new evidence for its potential translational clinical applications. Antioxid. Redox Signal. 00, 000–000.
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MICROCHEMICAL JOURNAL
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2025
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IF 5.1
Yu-Ping Wang,Peng-Xiang Yuan,Jing-Yuan Zhang,Bo Wang,Liu-Pan Yang,Li-Li Wang
For various physiopathological processes, ferroptosis is a unique form of regulatory cell death and has been confirmed to be closely related to intracellular viscosity fluctuations. The dysfunction of lysosome has been considered as one of the main causes of ferroptosis. For further understanding the occurrence and development of ferroptosis, it is of great significance to reveal the viscosity fluctuations of lysosome during ferroptosis. However, it is still lack of self-calibrating ratiometric probe with high accuracy and precision for effectively tracking the viscosity changes in lysosome during ferroptosis. In this work, a ratiometric fluorescent sensor based on the rhodol decorated carbon dots (m-CDs-Rho) was developed to track viscosity changes in lysosome during ferroptosis. The great capacity for targeting lysosome may be ascribed to the rich amino groups on the surface of m-CDs-Rho. The m-CDs-Rho nanosensor exhibits a sensitive linear response in the viscosity range of 6.33–718 cP with the advantages of high selectivity and remarkable photostability. The enhanced Förster resonance energy transfer (FRET) efficiency (increase from 5.4 % in PBS to 23.4 % in 90 % glycerol) and restricted motions of Rho are responsible for the ratiometric fluorescence response toward viscosity. Moreover, the well-separated fluorescence emission makes the developed nanosensor be suitable for high resolution bioimaging of the lysosomal viscosity. The cell imaging results suggest that m-CDs-Rho mainly distributed in lysosome, and the change of viscosity in the ferroptosis model are visualized successfully.
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Cancer Communications
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2026
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IF 28.4
Chenchen Hu,Feiming Hu,Changjian Shao,Yuanli He,Liping Su,Daimei Shi,Lingying Yu,Yuanjie Sun,Jing Wang,Xiyang Zhang,Hongtao Duan,Junqi Zhang,Yubo Sun,Dongbo Jiang,Xiaolong Yan,Shuya Yang,Kun Yang
Background: Lung cancer remains a major global health burden. RNA-binding proteins (RBPs) play crucial roles in post-transcriptional gene regulation, and their dysregulation is frequently implicated in tumorigenesis. The present study aimed to elucidate the molecular network governed by the highly expressed RBP TIMELESS in lung adenocarcinoma (LUAD) and determine its mechanistic role in LUAD progression. Methods: The Cancer Genome Atlas-LUAD, Gene Expression Omnibus, and single-cell RNA sequencing datasets were analyzed to identify aberrantly expressed RBP genes. The RBP gene TIMELESS exhibited the most significant effect on LUAD cell death and was selected for further study. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation sequencing and RNA sequencing were employed to identify ferroptosis-related targets directly bound by TIMELESS. Molecular mechanisms underlying the TIMELESS-mediated regulation of ferroptosis in LUAD were investigated via immunoprecipitation–mass spectrometry, glutathione S -transferase pull-down, immunofluorescence–fluorescence in situ hybridization, RNA immunoprecipitation, poly(A)-tail, and RNA stability assays. In an orthotopic lung cancer mouse model treated with erastin (a ferroptosis inducer) and programmed cell death protein 1 (PD-1) blockade, the role of TIMELESS in therapeutic response was assessed via flow cytometry and multiplex immunofluorescence (mIF). Infiltrating immune cells in LUAD were analyzed by tissue microarrays (TMAs) via mIF. Results: TIMELESS significantly affected LUAD cell proliferation and death, and TIMELESS knockdown significantly enriched RNA-binding and ferroptosis pathways. Transferrin (TF) was identified as a direct TIMELESS target governing ferroptosis. TIMELESS was revealed to bind Ccr4-Not transcription complex subunit 3 (CNOT3) to promote TF mRNA degradation. TIMELESS depletion combined with erastin and PD-1 blockade enhances efficacy, prolongs survival, increases T cell and M1 macrophage infiltration, and reduces M2 macrophage infiltration. Further, high TIMELESS expression was inversely correlated with ferroptosis marker 4-hydroxynonenal but positively correlated with programmed cell death ligand 1 (PD-L1), reduced T cell and M1 macrophage infiltration, and increased M2 macrophage infiltration. Conclusions: TIMELESS recruits CNOT3 to accelerate TF mRNA degradation, thereby suppressing ferroptosis and promoting LUAD growth. These findings suggest that the TIMELESS/TF regulatory axis may be a promising therapeutic target for LUAD.
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