JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Xiaoli Cui,Di Yang,Zhihong Zhang,Chunmei Wang,He Li,Jinghui Sun,Tianyu Zhang,Mengyang Wang
Ethnopharmacological relevance Forsythiae Fructus, a classic heat-clearing and detoxifying herb in traditional Chinese medicine (TCM), is widely used for inflammatory conditions. Its primary bioactive component, Forsythoside A (FTA), exhibits potent anti-inflammatory and antioxidant activities. Given that hypertensive nephropathy is characterized by chronic inflammation, oxidative stress, and fibrosis-hallmarks that correspond to “heat” and “toxin” pathologies in TCM theory-Forsythiae Fructus represents a rational candidate for HN therapy. However, the precise mechanisms by which FTA inhibits HN progression remain incompletely elucidated. Aim of the study This study aims to investigate the protective effects of FTA against Ang II-induced HN and to elucidate the underlying signaling mechanisms. Materials and methods We established HN models in C57BL/6 mice and NRK-52E cells using Ang II. The effects of FTA on renal injury were investigated through renal dysfunction indicators and tissue staining. RNA sequencing, molecular docking, CETSA and SPR technologies were employed to explore potential target sites and mechanisms of FTA in renal injury. Results FTA mitigated Ang II-induced renal injury by reducing renal dysfunction markers (Cr, BUN and Alb/Cr), restoring renal tissue architecture, and decreasing inflammatory markers ( Ilb, Il6, Tnf ), without exerting antihypertensive effects. RNA sequencing revealed associations with mTOR and ASCL1.Taken together, our in vivo and in vitro data reveal that FTA binds to ASCL1 and inhibits its activity, subsequently blocking the downstream CCNB1/mTOR pathway to confer renal protection. This inhibition promotes mitophagy and inhibits ferroptosis, ultimately alleviating renal injury. Conclusions This study confirmed that FTA can bind to ASCL1, targeting the ASCL1-CCNB1/mTOR pathway to protect the kidney from Ang II-induced injury, offering broad therapeutic prospects for the treatment of HN.
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MOLECULAR IMMUNOLOGY
·
2026
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IF 3.7
Suhong Ye,Ling Bao,Qiaolu Xu,Zihan Ding,Fei Wu,Xia Yuan,Yang Zhou,Nashwa Amin,Javaria Sundus,Marong Fang
Dihydroartemisinin (DHA) dose-dependently ameliorates ischemic brain injury and promotes neurological recovery in mice after ischemic stroke. • DHA inhibits ferroptosis in ischemic brain tissue via regulating iron homeostasis, lipid peroxidation and core ferroptosis-related proteins. • Astrocytic TAK1-CREB1 signaling pathway is identified as the key molecular target mediating the neuroprotective effects of DHA. • This study provides a promising drug repurposing candidate and novel therapeutic target for the clinical treatment of ischemic stroke. Background Ischemic stroke accounts for 87% of all stroke cases, and remains a leading cause of mortality and disability worldwide. Current reperfusion therapies are limited by narrow therapeutic windows, and cerebral ischemia-reperfusion injury (CIRI) remains a major clinical challenge. Ferroptosis, an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation, has been identified as a key pathological driver of CIRI. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has shown neuroprotective effects in ischemic stroke, but its underlying mechanism, especially the regulatory effect on ferroptosis via the TAK1-CREB1 signaling axis, remains unclear. Objective To investigate the neuroprotective effect of DHA in ischemic stroke and its molecular mechanism related to the TAK1-CREB1 signaling pathway and ferroptosis regulation. Methods Wild-type (WT) C57BL/6 J mice and astrocyte-specific CREB1 conditional knockout (CREB1 CKO) mice were used to establish a photothrombotic stroke (PTs) model. Neurological function was evaluated by modified neurological severity score (mNSS), Bederson score, Garcia scale and hanging test. Cerebral infarct volume was measured by TTC staining. Cerebral blood flow (CBF) was detected by laser speckle contrast imaging. Histopathological changes were observed by HE and Nissl staining. Mitochondrial ultrastructure was examined by transmission electron microscopy (TEM). The levels of malondialdehyde (MDA), glutathione (GSH), NADPH/NADP + ratio, ferrous iron (Fe 2+ ) and total iron in brain tissue were detected by biochemical kits. The expression of ferroptosis-related proteins and CREB1 was detected by Western blot and immunofluorescence staining. Results DHA treatment dose-dependently improved neurological function, reduced infarct volume, restored CBF, and ameliorated histopathological damage in PTs mice. TEM revealed that DHA reversed ferroptosis-typical mitochondrial changes in ischemic brain tissue. Biochemically, DHA decreased MDA, Fe²⁺, and total iron, while increasing GSH and NADPH/NADP⁺ ratio. Mechanistically, DHA dose-dependently upregulated GPX4, xCT, and FTH1, and downregulated ACSL4. Notably, astrocyte-specific CREB1 knockout nearly completely abolished DHA's neuroprotective and anti-ferroptosis effects. Conclusion DHA promotes neurological rehabilitation after ischemic stroke by targeting the astrocytic TAK1-CREB1 signaling pathway to inhibit ferroptosis. This study provides a novel theoretical basis and promising candidate drug for the clinical treatment of ischemic stroke.
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FASEB JOURNAL
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2026
·Vol. 40
·期 15
·e72061
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IF 4.3
Wei Liu,Yuqin Wang,Jiayuan Wu,Caihong He,Zhengwei Zhou
Lactate, a metabolic byproduct of glycolysis, accumulates during myocardial infarction and ischemia/reperfusion (I/R) injury, acting as both a metabolic stress marker and a signaling molecule that influences inflammation and cell fate. Lactate can induce histone lysine lactylation (Kla), a novel post‐translational modification that regulates gene transcription and immune responses. Despite this discovery, its role in I/R injury remains unclear. To investigate the effects of lactate and histone lactylation, both in vivo myocardial I/R injury and in vitro hypoxia/reoxygenation (H/R) injury models using cardiomyocytes were established. Lipid peroxidation, LDH, MDA, SOD, and iron levels were quantified using specialized fluorescent probes and commercial kits. MeRIP and RIP assays were performed to investigate WTAP, YTHDF1, and ALOX15 interactions. TEM was utilized to examine mitochondrial ultrastructure and morphology. Lactate levels were elevated in I/R rats, and reducing lactate levels effectively mitigated ferroptosis and myocardial injury. Furthermore, lactate promoted Kla of WTAP, resulting in upregulation of WTAP protein expression compared to the I/R group. Global m 6 A RNA methylation levels increased by lactate treatment. Elevated WTAP levels, or overexpression of YTHDF1, facilitated m6A modification of ALOX15 mRNA, leading to upregulation of ALOX15 expression and enhanced ferroptosis during I/R injury. Notably, overexpression of ALOX15 reversed the protective effects of WTAP knockdown. Finally, we validated the involvement of the WTAP‐YTHDF1‐ALOX15 regulatory axis in vivo. Lactate‐induced Kla of WTAP led to its upregulation, which, together with YTHDF1, facilitated the m6A modification of ALOX15 mRNA. This modification increased ALOX15 expression, triggering cardiomyocyte ferroptosis and worsening myocardial I/R injury. These findings highlight the potential of targeting lactate‐induced Kla and its downstream effectors, including WTAP, YTHDF1, and ALOX15, as therapeutic strategies. Lactate accumulation during myocardial ischemia–reperfusion injury enhances histone lactylation and WTAP expression, promoting m 6 A modification of ALOX15 mRNA through YTHDF1. This regulatory axis increases ALOX15 expression, lipid peroxidation, and ferroptosis, thereby aggravating myocardial injury. Targeting WTAP lactylation or the WTAP/YTHDF1/ALOX15 pathway may provide a potential therapeutic strategy for myocardial ischemia–reperfusion injury.
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International Journal of Nanomedicine
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2025
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IF 6.5
Rongrong Zhang,Shuting Lan,Mengxuan Jia,Fangyuan Liu,Mengqi Wang,Qin Jin,Liya Su,Gang Liu
Introduction The theranostic potential of taurine-derived carbon dots (Tau/CDs) in colorectal cancer (CRC) remains largely unexplored, despite their promising physicochemical and biological properties.Methods In this study, Tau/CDs were synthesized via a microwave-assisted irradiation method, employing citric acid as the carbon source, urea as the nitrogen source, and taurine (Tau) as the dopant. Comprehensive physicochemical characterization and biocompatibility assessments were performed both in vitro and in vivo. The anti-cancer efficacy of Tau/CDs against CRC was systematically evaluated through a series of functional assays, including cell viability, proliferation, migration, invasion, adhesion, clonogenicity, cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), and transcriptomic profiling. The therapeutic efficacy was further validated in vivo using CRC xenograft murine models.Results Tau/CDs exhibited excellent biocompatibility and significantly impaired key malignant properties of CRC cells, including viability, proliferation, migration, invasion, clonogenicity, and EMT. Treatment with Tau/CDs induced cell cycle arrest and apoptosis in vitro, while in vivo administration robustly suppressed tumor growth in xenograft models. Mechanistically, transcriptomic analysis combined with ferroptosis profiling identified Heme Oxygenase 1 (HO-1)-mediated ferroptosis as a critical pathway underlying the anti-tumor activity of Tau/CDs.Conclusion Microwave-assisted synthesis of Tau/CDs from citric acid, urea, and Tau yielded biocompatible nanoparticles with potent anti-cancer properties. Tau/CDs were shown to inhibit CRC progression by regulating multiple malignant phenotypes, with HO-1-mediated ferroptosis emerging as a critical mechanistic axis. These findings highlight Tau/CDs as a promising candidate for future clinical translation in CRC nanomedicine.
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BIOMATERIALS
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2025
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IF 12.9
Xinghua Yu,Lingan Zeng,Haiyan Chen,Xuemei Dong,Fan Wen,Mingming Wang,Runqi Pan,Yujun Zhang,Wei Zhu,Dingyuan Yan,Dong Wang,Fei Sun
Asthenozoospermia, a leading cause of male infertility characterized by impaired sperm motility, poses significant therapeutic challenges due to the restrictive blood-testis barrier (BTB). To address this limitation, we engineered multifunctional extracellular vesicles (EVs) derived from umbilical cord mesenchymal stem cells, loaded with adenosine triphosphate (ATP) to synergistically restore cellular bioenergetics and suppress ferroptosis. These EVs were further functionalized with an aggregation-induced emission luminogen for near-infrared-II (NIR-II) fluorescence imaging, enabling real-time visualization of their efficient BTB penetration and targeted accumulation within testicular tissues. Upon localization in the seminiferous tubules, the released ATP directly replenishes the energy reserves of spermatogenic cells and enhances sperm motility in asthenozoospermia models. Simultaneously, the EVs upregulate glutathione peroxidase 4, mitigating ferroptosis and synergizing with ATP to restore metabolic homeostasis. In vivo studies demonstrate the dual efficacy of this platform: the EVs precisely traverse the BTB while robustly inhibiting ferroptosis without systemic toxicity, significantly improving sperm count and kinematic parameters (motility, velocity). This study presents a multifunctional nanoplatform that integrates NIR–II–guided imaging, ATP-mediated energy restoration, and pathology-specific ferroptosis inhibition, providing a promising non-invasive therapeutic strategy for asthenozoospermia.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2025
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IF 9.7
Bowen Song,Ziye Zhao,Zhanhong Qiao,Ji Li,Dawei Chen,Ming Zhao,Haiyang Hu
Despite significant advancements in tumor immunotherapy, challenges including insufficient immunogenicity and immunosuppressive microenvironment continue to hinder therapeutic effect. The immunogenic cell death (ICD) enhances the tumor immune microenvironment and potentiate immunotherapy response. Certain chemotherapeutic agents can induce ICD; however, their limited immunogenicity, poor tumor-site targeting, and low tumor permeability restrict their efficacy. Herein, bacteria-driven liposomes were designed. Liposomes co-loaded with mitoxantrone (MTO) and iron ions (Fe 3+ ) were engineered to leverage the hypoxia-responsive properties of Escherichia coli Nissle 1917 (EcN) for precise tumor-site targeting. In the acidic tumor environment, mitoxantrone/ferric ions liposomes (LFM) released Fe 3+ and MTO. Intracellular Fe 3+ is reduced to Fe 2+ , catalyzing the Fenton reaction to generate reactive oxygen species (ROS) and induce ferroptosis. Concurrently, mitoxantrone (MTO) exerts direct cytotoxic effects on tumor cells. The synergistic interplay of these mechanisms significantly enhances the immunogenicity of tumor cells, triggering ICD and subsequently activating systemic antitumor immune responses. The drug delivery system constructed in this study integrated chemotherapy, ferroptosis, and immune activation, providing an innovative and effective strategy for tumor therapy. This approach paves the way for advanced combination therapies in cancer treatment.
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Journal of Advanced Research
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2025
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IF 13
Minyi Zhang,Qi Wang,Chen Li,Mengyao Chen,Chunhui Wang,Zikang Wang,Tao Xia,Chengqing Yi,Shuo Shi
Introduction Ion interference therapy has emerged as a promising new treatment for Osteosarcoma (OS). However, its efficacy is significantly restricted by inadequate hydrogen peroxide (H 2 O 2 ) under the complex tumor microenvironment (TME). Objectives This study aimed to supply sufficient H 2 O 2 to enhance tumor therapy efficacy and address the limitations associated with ion interference. Methods A hollow manganese dioxide (HMnO 2 ) nanoplatform loaded with calcium peroxide (CaO 2 ) (denoted as HMnO 2 @CaO 2 ) was evaluated for biosafety through hemolysis tests. The functionality of HMnO 2 @CaO 2 was further validated by quantitative real-time polymerase chain reaction (qRT-PCR) and cytometric analysis. Results Excessive Ca 2+ accumulation induces endoplasmic reticulum (ER) stress, enhances oxidative stress, and causes mitochondrial damage. Notably, Mn 2+ facilitates treatment monitoring through magnetic resonance imaging (MRI). Additionally, Mn 2+ -induced ferroptosis triggers an immune response that promotes the polarization of tumor-associated macrophages (TAMs), transforming the pro-tumoral M2 phenotype into the tumoricidal M1 phenotype, thereby enhancing the efficacy of immunotherapy. Conclusion In conclusion, HMnO 2 @CaO 2 nanoplatform enhances tumor therapy efficacy by overcoming ferroptosis limitations, inducing Ca 2+ overload, and boosting anti-tumor immunity. This strategy offers a promising approach to ion interference in the clinical translation of nanomedicines. Furthermore, it marks a significant advancement in osteosarcoma (OS) treatment and underscores the transformative potential of nanotechnology in medicine.
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Journal of Science-Advanced Materials and Devices
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2025
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IF 6.8
Kong Jiahui,Zhang Yongqiang,Yang Yuchang,Wang Ziheng,Jing Xiaohong,Lin Shuting,Chen Hongyue,Dong Xiaoxv,Qu Changhai,Cai Mengru,Ni Jian,Yin Xingbin
Malignant melanoma (MM) exhibits clinical traits of vigorous metastasis and an unfavorable prognosis. Traditional therapeutic modalities such as surgical resection, radiotherapy, and chemotherapy have restricted efficacy and notable side effects, thereby urgently demanding new drugs or treatment approaches. The iron-doped zeolite imidazole ester skeleton material (Fe-ZIF-8, FZ) exhibits outstanding biological safety and acid-responsive drug release properties, serving as an excellent nano-delivery carrier. Oridonin (Ori) is capable of inducing ferroptosis in tumor cells by targeting key genes (such as GPX4, SLC7A11, GGT1), and demonstrates a potent therapeutic effect on MM. Simultaneously, small interfering RNA (siRNA) can exert a role in gene silencing. In this study, we devised biomimetic nanoparticles (NPs) based on iron-doped zeolitic imidazolate framework-8 (FZ) for the co-delivery of Ori and siRNA targeting GPX4 (siRNA GPX4 ). FZ was employed to co-load Ori and siRNA targeting GPX4, the core regulator of ferroptosis, to play a role in drug and gene therapy for MM. The A375 tumor cell membrane was biomimetically modified to construct anti-tumor drug targeted delivery nanoparticles, thereby achieving efficient co-delivery of Ori and siRNA GPX4 . This provides a novel idea for the development of highly efficient and low-toxicity treatment of MM and the overcoming of tumor drug resistance.
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JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE
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2026
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IF 4.7
Hailong Feng,Hongtao Luo,Xiugeng Li,Yang Jiang,Baihui He
Ferroptosis is a novel anticancer therapeutic approach that effectively circumvents the apoptotic cell death mechanism. Nonetheless, enhancing the catalytic effectiveness of the Fe 2+ -mediated Fenton reaction and effectively inducing ferroptosis present significant challenges. In this study, motivated by the kinetics of hyperthermia-improved Fenton reactions, we initially developed Quercetin (QT)-Curcumin (CUR)-Iron (Fe)-coordinated nanochelates for photothermal-improved ferroptosis in anticancer therapy. We precisely adjusted the appropriate feeding rate of polyvinylpyrrolidone (PVP), QT, CUR, and Fe to develop unique nanofibrous QT-CUR-Fe chelates, referred to as QCFs. The differences in size and structure made QCFs more practical for colorectal cancer therapy than ultrasmall QT-Fe (QFs). Under NIR laser exposure, QCFs can continuously enhance the formation of depleted excessive GSH and toxic hydroxyl radicals (•OH), leading to increased lipid peroxidation (LPO) accumulation and subsequently activating the ferroptosis pathway in vitro. Furthermore, the incorporation of CUR may suppress prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) in conjunction with PTT-improved ferroptosis colorectal therapy to facilitate dendritic cell (DC) maturation, elicit immunogenic cell death (ICD), and enhance synergistic antitumor immunotherapy. Overall, this study proposed a way to integrate small-molecule immunomodulators into QFs nanocoordination to overcome its limitations, thereby fostering a novel design concept for colorectal cancer therapy.
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BIOORGANIC CHEMISTRY
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2026
·
IF 5.1
Yuting Liu,Tianyi Kang,Cuiping Shi,Fangfang Wei,Yixiu Zhong,Xin Hong,Jianglin Zhang,Kai Li
Exploring photosensitizers that efficiently generate oxygen-independent hydroxyl radical (•OH) and activate highly immunogenic PANoptosis and ferroptosis shows promise in addressing the limited efficacy of photodynamic immunotherapy (PDI) in the hypoxic and immunosuppressive tumor microenvironment (TME). However, challenges still exist due to the unsatisfactory •OH production efficiency in most organic photosensitizers and the unresolved relationship between •OH and PANoptosis. Here, we designed and synthesized two novel iridium(III) complexes, Ir1 and Ir2 . Notably, Ir1 produced more type I/II reactive oxygen species under light versus Ir2 and the clinically-used Chlorin e6 (Ce6), including a 25-fold higher •OH yield than both controls. Under extreme intracellular hypoxia, where superoxide anion (O 2 •- ) and singlet oxygen ( 1 O 2 ) were restricted, Ir1 maintained normoxia-equivalent •OH production, which endowed it with remarkable phototoxicity (IC 50 = 0.98 μM) and effective phototoxic index (PI = 3.05). Mechanistically, the •OH produced by Ir1 induced PANoptosis by increasing the expression of cleaved Caspase-3, GSDMD-N, and p-MLKL, and activated ferroptosis through the GSH-GPX4-LPO axis. Subsequently, Ir1 induced immunogenic cell death by enhancing the release of damage-associated molecular patterns under hypoxia, leading to a 1.8-fold increase in dendritic cell maturation. In melanoma-bearing mice, Ir1 achieved 89% reduction in tumor volume and transformed the immunosuppressed “cold” tumors to the inflamed “hot” phenotypes. This work establishes that the efficient •OH generation from iridium(III)-based photosensitizer can synergistically trigger PANoptosis and ferroptosis. This constitutes a viable approach for achieving effective PDI in hypoxic and immunosuppressive TME.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2026
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IF 12.6
Hao Zhang,Xiaoyu Song,Leilei Zhao,Chenlong Wang,Shen Chen,Yinghui Wang,Li Zhang,Fangyi Xu,Hongjie Zhang,Qilong Wang,Chao Luo
Photodynamic therapy (PDT) holds significant potential for tumor treatment, yet its immunotherapeutic efficacy is severely constrained by the immunosuppressive tumor microenvironment (TME) marked by lactate accumulation, hypoxia, and glutathione (GSH) overexpression. To overcome these limitations, we engineered an injectable hydrogel system (FPH@A/C) that synergistically integrates oxygen-independent PDT, ferroptosis activation, and lactate metabolic reprogramming to remodel immunosuppressive TME and potentiate antitumor immunity. The hydrogel comprises singlet oxygen-preloaded iron-based nanoparticles (FPH), lithium carbonate (LC), and sodium alginate (ALG), rapidly crosslinking into a stable matrix when encountering physiological Ca²⁺ concentration for localized therapeutic delivery. Within TME, GSH-triggered FPH degradation releases Fe²⁺ and pre-stored singlet oxygen, enabling chemodynamic therapy (CDT) and photo-independent PDT to induce tumor ferroptosis. Simultaneously, LC reprograms lactate-a metabolic byproduct-into an energy substrate for CD8⁺ T cells, counteracting lactate-driven immunosuppression. Notably, combining FPH@A/C with immune checkpoint blockade (ICB) therapy demonstrates synergistic effects, robustly enhancing dendritic cell maturation and cytotoxic T lymphocyte infiltration. This multifunctional platform establishes a novel paradigm for colorectal cancer immunotherapy by concurrently addressing metabolic constraints and immune evasion mechanisms.
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LIFE SCIENCES
·
2026
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IF 5.1
Pan Huang,Kexin Zhang,Ying Chen,Jiaxin Cheng,Shuangshuang Yang,Lin Shi,Yajuan Wang,Qin Zhang
Elevated homocysteine (Hcy) is an independent risk factor for hypertension, and kidney is an important organ for Hcy metabolism and blood pressure regulation, and its damage is closely related to the process of hypertension. Recent evidence suggests that ferroptosis, an oxidative stress-related form of cell death, contributes significantly to hypertensive organ damage. However, whether Hcy aggravates renal injury in H-type hypertension by destroying renal hydrogen sulfide (H 2 S) metabolism and driving ferroptosis is still lack of direct evidence. In this study, the H-type hypertensive rat model induced by high methionine diet combined with HK-2 cell model was studied. We observed a significant increase in blood pressure and plasma Hcy in the Hcy group, accompanied by renal dysfunction and renal tubular injury. Specifically, in the renal tissue of Hcy group rats, the levels of KIM-1, Fe 2+ and malondialdehyde (MDA) were increased, glutathione/glutathione disulfide (GSH/GSSG) ratio decreased, SLC7A11 expression was down-regulated, and GPX4 activity was inhibited. Concurrently, H 2 S levels and cystathionine-beta-synthase (CBS) activity were decreased. In vitro experiments using HK-2 cells confirmed that Hcy could down-regulate the expression of CBS, cystathionine-gamma-lyase (CSE), SLC7A11, GPX4 and GSH/GSSG ratio, and up-regulate MDA and reactive oxygen species (ROS) levels. Treatment with H 2 S donor (NaHS) or ferroptosis inhibitors (Ferrostatin-1, Fer-1) could rescue these changes. Collectively, our results demonstrate that high Hcy promotes hypertension by suppressing endogenous H 2 S generation, downregulating the SLC7A11/GPX4 signaling axis, and inducing ferroptosis. These findings reveal a new mechanism by which Hcy aggravates hypertension by inhibiting H 2 S synthesis and inducing ferroptosis.
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