CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Boxin Chen,Xiaoliang Deng,Lina Wu,Zhihui Zheng,Shiying Xu,Xiaowei Lin,You Wu,Hanxing Lin,Zhihong Liu,Xianquan Feng
Carrier-free IHA NPs achieve multi-drug delivery with nearly 100% loading efficiency. • O 2 supply and consumption restriction alleviate hypoxia to sensitize phototherapy. • Phototherapy-ferroptosis remodels immune microenvironment to boost TNBC αPD-L1 therapy. • Combined therapy inhibits primary/distant tumor growth and lung metastasis in TNBC. Triple-negative breast cancer (TNBC) is featured by high malignancy, poor prognosis, and the absence of effective clinical targeted therapies. Although αPD-L1 immunotherapy blocks tumor immune escape and activates systemic antitumor immunity, its efficacy is limited by low tumor immunogenicity and a hypoxic microenvironment. Phototherapy effectively elevates tumor immunogenicity, whereas it further deteriorates the hypoxic tumor microenvironment. Herein, an O₂-economized phototherapy-ferroptosis synergistic nanoplatform was engineered to strengthen αPD-L1 immunotherapy against TNBC. Specifically, indocyanine green (ICG), hemin and atovaquone (ATO) are self-assembled into carrier-free nanoparticles (IHA NPs) to enhance intratumoral drug accumulation. ICG acts as a photosensitizer, which achieves tumor ablation through synergistic photothermal and photodynamic therapy, induces immunogenic cell death, and enhances tumor immunogenicity. Furthermore, hemin achieves in situ oxygen generation and simultaneously triggers ferroptosis, while ATO inhibits mitochondrial oxidative phosphorylation and reduces oxygen consumption. The two agents construct a synergistic strategy of oxygen supplementation coupled with oxygen consumption restriction, thereby remodeling the hypoxic tumor microenvironment and collaboratively enhancing phototherapeutic efficacy. Combination of IHA NPs with αPD-L1 efficiently suppresses the growth of primary TNBC tumors, distant tumor lesions and pulmonary metastases, and enhances the infiltration of cytotoxic T lymphocytes as well as the formation of effector memory T cells. This study provides novel insights into immunotherapy for TNBC. Download: Download high-res image (101KB) Download: Download full-size image
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PHYTOMEDICINE
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2026
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IF 11.3
Minghui Zhao,Hongfang Mu,Qian Ji,Jiale Song,Fuyixuan Zheng,Tianlong Liu,Wenbin Li,Rong Wang
Background The effects of persistent hypoxic conditions in high-altitude regions on metabolic disorders remain poorly understood and in-depth investigation into its underlying molecular mechanisms is notably insufficient. As a metabolism-associated liver disease, the pathogenesis of non-alcoholic fatty liver disease (NAFLD) under hypoxic conditions urgently requires clarification. Previous studies have demonstrated that resveratrol (Rsv) possesses significant anti-inflammatory, antioxidant, and lipid metabolism-modulating properties, and it can act as an inhibitor of ferroptosis. Yet its precise therapeutic efficacy and mechanism in hypoxic NAFLD remain to be further explored. Objective This study aims to explore the potential mechanism by which Rsv improves the deterioration of NAFLD under hypoxia exposure. Methods Herein, we performed concurrent interventions in both in vivo and in vitro models of NAFLD, comprehensively detecting biochemical indicators (inflammatory factors, oxidative stress markers, liver function), liver histopathological changes, and nucleic acid levels to assess the effects of Rsv. By introducing ferroptosis modulators, we measured core ferroptosis parameters (mitochondrial ultrastructure, Fe²⁺, 4-HNE, LPO levels, and key protein expressions) to define disease progression patterns. By HIF-1α silencing was employed to verify its regulatory roles in ferroptosis-related factors and NAFLD pathogenesis. Co-Immunoprecipitation assays and immunofluorescence co-localization were used to explore protein interactions among ACSL4, TfR1, and HIF-1α. Conclusion Our results demonstrated that high-altitude hypoxia exacerbates NAFLD via inducing ferroptosis; HIF-1α upregulates the expression of key ferroptosis mediators (ACSL4, TfR1), and HIF-1α silencing attenuates ferroptosis. Rsv exerts therapeutic effects against hypoxia-related NAFLD by targeting the HIF-1α-mediated ferroptosis pathway. This study elucidates the pivotal role of HIF-1α-dependent ferroptosis in hypoxia-aggravated NAFLD, identifies the therapeutic targets and mechanisms of Rsv, and provides novel theoretical foundations and potential intervention strategies for clinical management of hypoxia-related NAFLD in high-altitude areas.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.2
Yanan Zhao,Rui Wang,Ziyang Huang,Siting Ju,Binghua Dong,Hui Teng,Lei Chen
The gut is often referred to as the “second brain” and is highly vulnerable to alcohol exposure. Galangin, a flavonoid extracted from traditional medicinal herbs, Alpinia officinarum Hance, has manifested auspicious clinical application potential. This study aims to explore the regulatory effect of galangin on ferroptosis in an alcohol-related intestinal injury model and its underlying mechanism. In vivo, we confirmed that galangin administration could alleviate alcohol-induced iron metabolism dysfunction and ferroptosis and activate the SESN2/KEAP1/NRF2 signaling pathway in mice colon. In vitro, alcohol-caused disruption of iron homeostasis and ferroptosis could also be significantly reduced by galangin. Using specific small interfering RNA targeting SESN2 (Si-SESN2) or the NRF2 inhibitor ML385 significantly abrogated the protective effect of galangin. Molecular docking and Co-IP results further revealed that galangin activates NRF2 nuclear translocation by promoting KEAP1/SESN2 formation as well as KEAP1/NRF2 dissociation. Collectively, galangin suppressed ferroptosis by activating the SESN2/KEAP1/NRF2 pathway in mice and Caco-2 cells.
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MICROCHEMICAL JOURNAL
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2026
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IF 5.2
Shizeng Pei,Huiling Wang,Jing Liu,Gang Nie,W.M.W.W. Kandegama,Chunrong Liu
Sulfur dioxide (SO₂), as well as microenvironmental viscosity and polarity are indispensable for redox equilibrium, biomolecular trafficking, and metabolic signaling, yet holistic analysis tools are lacking. Herein, we developed a multifunctional fluorescent probe TPA-TOB for simultaneous detection of polarity, viscosity, and SO₂. In the D-π-A structured TPA-TOB , triphenylamine (TPA) functioned as the donor, with 2-thiobarbituric acid serving as the acceptor, linked by a thiophene vinyl π-bridge. This architecture targeted lipid droplets (LDs), while the C C bond served as the site of the Michael addition reaction for the recognition of SO 2 . The D-π-A structure of TPA-TOB with twisted intramolecular charge transfer (TICT) characteristics enabled it to respond to polarity and viscosity (≥620 nm fluorescence enhancement with higher viscosity/lower polarity). For SO₂, TPA-TOB exhibited 47-fold fluorescence enhancement at 420 nm (response time ~ 10 min, LOD 0.87 μM), with 95.78%–100.58% recovery for SO₂ detection in rock sugar. Furthermore, TPA-TOB facilitated dynamic monitoring of intracellular SO 2 redox dynamics and fluctuation of LDs microenvironment (polarity and viscosity) spanning cell, tissue, and organism levels. Significantly, we realized the dual-channel mapping of acute alcoholic liver injury (AALI) with this probe, as well as identification of pathological signatures in cancer, inflammation, and ferroptosis. Therefore, we have established an integrative analytical platform to elucidate the interplay between SO 2 signaling and LDs microenvironment, thereby deepening the understanding of their roles in the pathogenesis of multiple diseases, and providing novel avenues for mechanistic investigation and therapeutic discovery.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 4.7
Zhenshuai Zhang,Li Jiang,Lu Chen,Xinyan Cai,Yuteng Wang,Wenqian Xue,Kaijian Lei,Tianxiao Wang
Colorectal cancer (CRC) remains one of the most prevalent malignancies globally, with limited therapeutic options for advanced-stage patients due to acquired drug resistance and systemic toxicity. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for CRC, while cystathionine γ-lyase (CSE)—a key enzyme in hydrogen sulfide (H 2 S) biosynthesis—plays a critical role in maintaining redox homeostasis and suppressing ferroptosis in cancer cells. Here, we synthesized a novel small-molecule compound, DPhA-EtOBz-TSC, and systematically evaluated its anti-CRC efficacy and underlying molecular mechanism. The chemical structure of DPhA-EtOBz-TSC was confirmed by 1 H nuclear magnetic resonance ( 1 H NMR), 13 C NMR, and high-resolution mass spectrometry (HRMS). In vitro studies using human CRC cell lines (HCT8 and SW480) demonstrated that DPhA-EtOBz-TSC specifically targeted and inhibited CSE: molecular docking and cellular thermal shift assay (CETSA) confirmed direct binding between DPhA-EtOBz-TSC and CSE (binding affinity ΔG = −29.07 ± 3. 85 kcal/mol), while Western blot analysis revealed a concentration-dependent reduction in CSE protein levels in SW480 and HCT8 cells treated with DPhA-EtOBz-TSC. Mechanistically, DPhA-EtOBz-TSC-induced CSE downregulation disrupted the CSE-H 2 S-GPX4 axis, leading to reduced glutathione (GSH) levels, decreased glutathione peroxidase 4 (GPX4) activity, and accumulation of lipid reactive oxygen species (ROS) and malondialdehyde (MDA)—hallmarks of ferroptosis. Additionally, Electron microscopy and JC-1 staining revealed that DPhA-EtOBz-TSC induced significant alterations in mitochondrial morphology and a marked reduction in mitochondrial membrane potential (ΔΨm). Functionally, DPhA-EtOBz-TSC exhibited potent in vitro anti-CRC activity with IC 50 values of 25.15 μM (HCT8) and 26.11 μM (SW480) respectively, and suppressed migration and invasion. In vivo, DPhA-EtOBz-TSC (10 mg/kg/day, i.p.) significantly suppressed the growth of CT26 cell-derived xenograft tumors in BALB/c mice without causing obvious histopathological abnormalities in major organs (heart, liver, spleen, lung, kidney). Immunohistochemical staining of tumor tissues confirmed increased lipid peroxidation and decreased CSE/GPX4 expression in DPhA-EtOBz-TSC-treated mice, consistent with in vitro findings. In conclusion, DPhA-EtOBz-TSC is a novel CSE-targeting compound that induces ferroptosis in CRC cells and inhibits tumor growth in vivo. Our findings identify DPhA-EtOBz-TSC as a potential lead compound for CRC therapy and highlight the CSE-H 2 S-GPX4 axis as a viable therapeutic target for ferroptosis-based anticancer strategies.
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Experimental and Therapeutic Medicine
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2026
·Vol. 32
·期 4
·1-10
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IF 2.2
Wen Ouyang,Jianxin Gao,Jing Liu,Lulu Qin,Bang Liu,Ying He,Dai Zhou
Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.
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APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY
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2026
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IF 3.5
Li Yuejin,Ouyang Yiming,Zhu Yu,Hou Dezhi,Li Xing,Guo Xiaodong,Sheng Ping,Wu Hailong,Liao Yingzhong,Gong Kunmei,Li Linhai
Natural killer (NK) cells play a crucial role in combating gastric cancer (GC). However, they undergo ferroptosis in the tumor microenvironment of GC, which weakens their antitumor effects. Exosomal circRNA influences GC progression. Previous studies have reported the cancer-promoting role of circPDSS1 in GC, but whether it is involved in NK cell ferroptosis remains unclear. This study aimed to investigate the role of GC cell-derived exosomal circPDSS1 in NK cell ferroptosis. A noncontact coculture system of GC cells (HGC-27, AGS, and MKN-45 cells) and human NK-92 cells was established, and humanized mouse and cell-derived xenograft (CDX) tumor models were constructed for joint investigation. Cell death and viability were assessed via flow cytometry, LDH release assays and CCK-8 assays; circPDSS1 stability was determined by agarose gel electrophoresis and actinomycin D treatment; ferroptosis was determined by measuring lipid ROS, MDA, and Fe 2+ levels; and key molecular interactions were determined by performing dual-luciferase reporter assays and RIP and RNA pull-down experiments. CD56 and CD16 expression was reduced in clinical tumor tissues. In vitro experiments revealed that the proportion of 7-AAD + NK-92 cells cocultured with GC cells was significantly increased, accompanied by increased cell mortality and decreased IFN-γ and TNF-α secretion. Further studies revealed that circPDSS1 expression was abnormally elevated in GC tissues and cells and was particularly enriched in MKN-45 cell-derived exosomes (Exos). Knockdown of circPDSS1 alleviated MKN-45-Exo-induced cell damage; reduced lipid ROS, MDA, and Fe 2+ levels in NK-92 cells; and delayed tumor progression. Furthermore, a ferroptosis inhibitor suppressed circPDSS1 overexpression-induced cell death. Mechanistically, circPDSS1 sponged miR-142-3p to upregulate ACSL4 expression, promoting NK cell ferroptosis. Exosomal circPDSS1 derived from GC cells contributes to NK cell ferroptosis by sponging miR-142-3p to increase ACSL4 expression and exacerbate GC.
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ACS Applied Materials & Interfaces
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2026
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IF 7.8
Li Kaiming,Zhu Xiaole,Wu Haisi,Li Jiang,Wu Fan,Zhang Jianjun,Cai Jiayi,Shi Zheng,Zhang Xingguo,Xie Shengyang,Xie Rui
Triple-negative breast cancer (TNBC) tends to exhibit extremely large rates of tumor recurrence and mortality owing to the absence on effective therapeutic targets. Paclitaxel is the chemotherapeutic drug of choice, but the clinical efficacy in TNBC is limited. In the present study, we developed a folic acid (FA)-modified red blood cell membrane biomimetic drug delivery system encapsulating both paclitaxel and artesunate (PA@LRM-FA) against TNBC, aimed at enhancing ferroptosis and promoting immunogenic cell death to improve paclitaxel efficacy. The morphology, particle size, zeta potential, particle stability, paclitaxel and artesunate loading capacity, and paclitaxel and artesunate encapsulation efficiency of the formulations were studied. Through a cellular assay, we discovered that PA@LRM-FA inhibited the 4T1 cell proliferation, induced ROS accumulation, and promoted ferroptosis and immunogenic cell death. In tumor-bearing mice, PA@LRM-FA effectively targeted tumor tissues for the delivery of paclitaxel and artesunate and significantly induced ferroptosis, promoting immunogenic cell death and active immune cells in 4T1 tumors, resulting in a marked inhibition of tumor growth. Taken together, this work demonstrated a feasible therapeutic approach to inhibit TNBC by enhancing tumor ferroptosis and immunogenic cell death through PA@LRM-FA delivery of paclitaxel and artesunate.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2026
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IF 5.2
Shuoye Yang,Li Su,Suxi Liu,Siyu Zheng,Beibei Zhang,Xin Wang,Ning Li,Lu Zhang,Peng Li
The combination of ferroptosis with chemotherapy and immunotherapy is a novel cellular mechanism with significant implications for antitumor therapeutic strategies. It can mitigate toxic damage to normal tissues and cells, while potentiating antitumor immune responses. In this study, we propose a multi-mechanism nanosystem that utilizes amino-modified mesoporous silica (MSNs-NH 2 ) as carriers. These nanoparticles are loaded with doxorubicin (DOX) and the immunomodulator all-trans retinoic acid (ATRA), followed by coating with polydopamine (PDA). A hybrid nanosystem featuring a core/shell structure was fabricated by chemically chelating ferrous lactate onto PDA coating. It was subsequently conjugated with RGD-targeting peptides (RFP/MN@D/A). In vitro experiment results revealed that RFP/MN@D/A possessed pH/H 2 O 2 dual-responsive drug release characteristics, and could be efficiently internalized by MCF-7 cells. Exogenous Fe 2+ activated the Fenton reaction in the acidic tumor microenvironment (TME), generating an abundance of reactive oxygen species (ROS) that attack membrane phospholipids. This attack led to cytotoxic free radical production and thereby induced ferroptosis. Additionally, following gradual rupture of the PDA coating, DOX and ATRA were released responsively. This release triggered immunogenic cell death (ICD) and apoptosis through multiple mechanisms, including HMGB1 release, cell cycle arrest, and mitochondrial dysfunction. In tumor-bearing mice, RFP/MN@D/A exhibited superior tumor growth inhibitory activity alongside good biosafety profiles. Collectively, the functionalized delivery system developed in this study has significant potential for modulating immune responses and inducing ferroptosis through targeted delivery coupled with multiple responsive release strategies. This approach synergizes effectively with chemotherapy to achieve enhanced therapeutic efficacy against breast tumors, with broad application prospects for solid cancer treatment. Download: Download high-res image (419KB) Download: Download full-size image
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Stem Cell Research & Therapy
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2026
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IF 7.8
Li Xiao-huan,Lian Fu-wei,Lv Feng,Luo Xiao-Ling,Hu Bang-li,Zhang Li-tu,Ning Shu-fang
Background Mesenchymal stem cells (MSCs)-derived exosomes present great potential as nanocarriers for targeted drug delivery. Moreover, the therapeutic efficacy of exosomes can be substantially enhanced through functional modifications and the incorporation of bioactive molecules. Methods In this study, the MSCs were cultured under two-dimensional (2D) and three-dimensional (3D) cell culture conditions. The culture supernatants were collected for isolating exosomes. The characteristics and yields of exosomes from 2D and 3D cultures were detected by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), western blot analysis, and bicinchoninic acid (BCA) assay. Subsequently, 3D exosomes were loaded with miR-99b-5p and modified with iRGD peptide were formed into a new engineered exosome, designated as iRGD-Exo-miR-99b-5p. The effects of these engineered exosomes on the progression of colorectal cancer (CRC) were assessed through a series of in vivo and in vitro experiments. Results The 3D-cultured MSCs exhibited a higher yield of exosomes and enhanced uptake by CRC cells. Further in vitro experiments demonstrated that 3D-exosomes loaded with miR-99b-5p effectively inhibit the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of CRC cells. Results from a xenograft tumor model indicate that iRGD-modified exosomes were significantly enriched at tumor sites. Furthermore, exosomes modified with iRGD and loaded with miR-99b-5p were employed for CRC treatment, resulting in substantial tumor growth inhibition and enhanced the chemotherapy efficacy of 5-fluorouracil (5-FU) in vivo, without inducing notable toxicity or side effects. Mechanistically, exosome-mediated delivery of miR-99b-5p downregulated FGFR3 expression, thereby inhibiting the activation of the PI3K/AKt signaling pathway and promoting ferroptosis, ultimately attenuating CRC progression. Conclusions Collectively, iRGD-modified 3D exosomes loaded with miR-99b-5p were able to specifically target tumor sites, thereby significantly suppressing CRC growth through the induction of ferroptosis via regulating the FGFR3/PI3K/AKt signaling pathway. These findings suggest that functional engineering and bioactive loading of 3D-exosomes derived from MSCs represent a promising strategy for targeted cancer therapy. Graphical
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高影响因子
Scientific Reports
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2026
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IF 4.9
Cui Yongping,Guo Xiaoling,Xu Jingqi,Jia Xiang,Fan Jiaxin,Xu Tianjie,Li Yueyuan,Zhao Xingwang,Liu Kainan,Wei Zifeng,Zhang Hui,Cao Yanhua,Wang Zhiqiang,Wang Qian
Parkinson's disease (PD) is a common neurodegenerative disorder with a complex pathogenesis linked to ferroptosis, apoptosis, inflammation, and oxidative stress. Mounting evidence has demonstrated that the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is deeply involved in PD pathogenesis and acts as a key regulator of ferroptosis. Crocin, a carotenoid from saffron, exhibits potent neuroprotective effects in neurodegenerative diseases, particularly its anti-ferroptotic activity, alongside anti-apoptotic, anti-inflammatory, and antioxidant properties, though its precise molecular mechanisms remain unclear. Against this background, the present study aimed to explore the regulatory role of the mTOR pathway in rotenone (ROT)-induced ferroptosis and PD progression in rats, and to further investigate whether crocin exerts neuroprotection by targeting this signaling pathway and inhibiting ferroptosis. Male Sprague–Dawley rats were randomized into control, ROT, and Crocin + ROT groups. The ROT group received subcutaneous ROT (1.5 mg/kg/day) for 21 days to induce chronic PD; the Crocin + ROT group was gavaged with crocin (30 mg/kg) 2 h before each ROT injection. Subsequently, behavioral performance (open field, rotarod, and balance beam tests), striatal dopamine, reactive oxygen species (ROS), and 4-hydroxynonenal (4-HNE) levels (enzyme-linked immunosorbent assay, ELISA), substantia nigra (SN) histopathology (hematoxylin–eosin and Nissl staining), tyrosine hydroxylase (TH) immunohistochemistry, mitochondrial ultrastructure (transmission electron microscopy), glutathione (GSH), malondialdehyde (MDA), and Fe 2 ⁺ levels, and AKT/mTOR-related protein expression (Western blotting) were assessed. ROT induced motor dysfunction, reduced striatal dopamine levels, reduced TH-positive neurons in the SN, caused ferroptosis-like mitochondrial ultrastructural alterations, disrupted redox and iron homeostasis, and dysregulated the AKT/mTOR pathway ( P < 0.05 ). Crocin intervention significantly reversed these changes ( P < 0.05 ). Collectively, these findings suggest that crocin exerts neuroprotective effects in ROT-induced PD rats, possibly through modulation of the AKT/mTOR pathway and attenuation of ferroptosis and apoptosis.
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JOURNAL OF MEDICINAL CHEMISTRY
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2026
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IF 7.3
Yijing Shu,Yuheng Jiang,Ying Xiong,Sheng Huang,Chen Lunjie,Wen Ye,Yao Jian,Yimou Gong,Bowen Lei,Dong Yi,Dan Zhang,An Guo Wu,Siping Wei,Qiang Fu,Xia Zhou
Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation. Inhibiting ferroptosis has emerged as a promising therapeutic strategy, but existing inhibitors suffer from limited chemical diversity and suboptimal drug-likeness. Here, we report 1,3-disubstituted indolizine derivatives as novel noncanonical ferroptosis inhibitors. Through phenotypic screening and SAR optimization, we identified D12 (3-(2-methylbenzoyl)indolizine-1-yl acetate). D12 exhibits nanomolar potency (EC50 = 39.7 nM) in RSL3/erastin-induced PC12 cells, outperforming Fer-1. Mechanistically, D12 acts independently of iron chelation, radical trapping, or direct Nrf2 activation; instead, it alleviates oxidative stress and lipid peroxidation upstream. Compared to Fer-1, D12 displays improved metabolic stability, markedly higher systemic exposure, and robust brain penetration (brain/plasma ratio = 6.31). In vivo, D12 attenuates acetaminophen-induced liver injury and cerebral ischemia-reperfusion injury. These findings establish D12 as a mechanistically distinct, drug-like preclinical candidate and. highlight the indolizine scaffold as a promising new chemotype for ferroptosis-targeted drug discovery.
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