Cell Death & Disease
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2026
·Vol. 17
·期 1
·218
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IF 12.2
Zhang Ziyun,Li Yi,Hu Jingjiang,Tang Xingjie,Li Zhanpeng,Sun Xiaoyan,Feng Dade,Yao Yixin,Mao Chao,Tao Yongguang,Xie Li,Luo Huaiqing,Li Yufei,Yu Xing,Peng Xiaoning,Cong Li,Jiang Yiqun
Oral squamous cell carcinoma (OSCC) is an aggressive malignancy characterized by poor prognosis, largely attributable to cancer stem cell (CSC) persistence and ferroptosis resistance. However, the molecular mechanisms that coordinately regulate stemness maintenance and ferroptosis suppression in OSCC remain insufficiently characterized. In this study, KIF20A was identified as significantly overexpressed in OSCC and strongly correlated with adverse clinical outcomes. An integrative approach identified DHX9 as a candidate interactor of KIF20A. Mechanistic investigations revealed that KIF20A regulates DHX9 nucleocytoplasmic distribution and inhibits TRIM21-mediated K48-linked polyubiquitination at DHX9-K755, thereby preventing its proteasomal degradation and enhancing protein stability. Elevated DHX9 enhanced SOX2 mRNA stability, leading to upregulation of SOX2, a central regulator of both CSC maintenance and ferroptosis resistance. Functionally, KIF20A promoted CSC phenotypes, inhibited ferroptosis in vitro and in vivo, and activated the PI3K/AKT signaling pathway. Notably, treatment with ENMD-2076 (identified through Connectivity Map analysis) significantly reduced KIF20A expression, attenuated CSC characteristics, augmented cisplatin sensitivity, and exerted marked antitumor activity. These findings elucidate a novel KIF20A-DHX9-SOX2 regulatory axis that simultaneously governs CSC maintenance and ferroptosis evasion in OSCC. Targeting KIF20A, either as a monotherapy or in combination with chemotherapy, may offer a promising strategy to improve therapeutic outcomes in OSCC.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2026
·
IF 9.6
Nianting Xiao,Xiao He,Daxiu Li,Yu Liu,Xiao Guo,Chunyuan Gan,Robert J. Lee,Jing Xie,Chong Li,Yaqin Tang
One-pot biomineralization co-encapsulates ART and GOx, overcoming delivery paradoxes. • RBCm coating prolongs circulation and enhances tumor accumulation. • GOx-driven starvation generates acidity, which in turn amplifies ART-mediated Fenton-like ROS production. • Released Zn 2+ sensitizes ferroptosis via a dual FPN1/p53 regulatory axis. • The integrated metabolic-oxidative strike suppresses aggressive breast cancer growth in vivo. Breast cancer presents a formidable global health challenge, with traditional monotherapies frequently hampered by limited specificity and off-target toxicity. Herein, we developed a highly integrated, biomimetic, and pH-responsive zeolitic imidazolate framework-8 (ZIF-8) nanoplatform, RBCm-coated nanoparticles (R-A/G@Z), tailored for cascaded starvation and potentiated ferroptosis therapy. Through a one-pot biomineralization approach, the hydrophobic ferroptosis inducer artesunate (ART) and the hydrophilic metabolic enzyme glucose oxidase (GOx) were co-encapsulated within a ZIF-8 framework, followed by red blood cell membrane (RBCm) surface cloaking. The R-A/G@Z platform demonstrates enhanced tumor accumulation and undergoes acid-triggered disassembly within the tumor microenvironment (TME). Upon internalization, GOx-mediated glucose oxidation serves to starve the tumor of its primary energy source while continuously generating hydrogen peroxide (H 2 O 2 ) and protons. This localized acidification accelerates structural degradation, supplying ample H 2 O 2 to fuel an ART-triggered Fenton-like reaction. Crucially, the concurrent liberation of Zn 2+ from the ZIF-8 lattice orchestrates a dual-regulatory axis: it downregulates ferroportin 1 (FPN1) to retain reactive iron intracellularly, and upregulates tumor protein p53 (p53) to suppress the solute carrier family 7 member 11-glutathione-glutathione peroxidase 4 (SLC7A11-GSH-GPX4) antioxidant shield. This integrated strategy overcomes the tumor's redox defenses, leading to ferroptotic cell death. In vitro and in vivo evaluations confirm that R-A/G@Z effectively suppresses aggressive breast tumors while maintaining a good safety profile, offering a promising strategy for intelligent metabolic-chemodynamic cancer nanomedicine. pH-responsive R-A/G@Z co-delivers GOx and ART. GOx depletes glucose to generate H + and H 2 O 2 , accelerating ZIF-8 degradation and fueling ART-mediated Fenton reaction. Released Zn 2+ downregulates FPN1 to trap iron and upregulates p53 to suppress SLC7A11-GPX4, triggering synergistic ferroptosis in breast cancer. Download: Download high-res image (164KB) Download: Download full-size image
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Materials Today Bio
·
2026
·
IF 11
Pan Yang,Shuai He,Mingdong Xu,Yanying Sun,Jingyi Gao,Jian Chen,Tongtong Niu,Liguo Hao
Pancreatic cancer responds poorly to conventional chemotherapy, largely because of the pronounced resistance of tumor cells to chemotherapy-induced apoptosis. Ferroptosis, a non-apoptotic form of programmed cell death, has emerged as a promising strategy to overcome this resistance. However, its therapeutic efficacy is often limited by insufficient hydrogen peroxide (H 2 O 2 ) and excessive glutathione (GSH) in the tumor microenvironment (TME). Herein, we developed a nanoplatform, HM-MnO 2 @DOX/CaO 2 @PDA/HA (HMDCPH), using hollow mesoporous manganese dioxide (HM-MnO 2 ) as a carrier to co-deliver doxorubicin (DOX) and calcium peroxide (CaO 2 ). The crosslinked PDA/HA shell enhanced both the tumor-targeting capability and biocompatibility of the nanoplatform. In the TME, HM-MnO 2 depleted GSH and promoted reactive oxygen species (ROS) generation, whereas CaO 2 decomposition generated H 2 O 2 and released Ca 2+ , inducing mitochondrial calcium overload and further aggravating oxidative stress. These synergistic effects enhanced lipid peroxidation (LPO) and exacerbated ferroptosis-related oxidative damage. Moreover, the near-infrared (NIR)-triggered photothermal effect further strengthened the antitumor efficacy of HMDCPH. In addition, nanoplatform degradation released Mn 2+ , enabling T 1 -weighted magnetic resonance imaging (MRI). Collectively, this study presents a synergistic nanotherapeutic strategy that integrates chemotherapy, photothermal therapy, and ferroptosis-related mechanisms to overcome chemoresistance in pancreatic cancer.
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Frontiers in Medicine
·
2026
·
IF 3.6
Jiajia Sang,Zixiang Jin,Hui Zuo,Long Zeng,Yi Yue,Meng Wang,Jun Hu,Feng Hao
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, fibroblast-like synoviocyte hyperplasia, and progressive cartilage and bone destruction. Moxibustion is widely used as a non-pharmacological adjunctive intervention for RA; however, its specific therapeutic effects and its associations with autophagy and ferroptosis remain insufficiently characterized. This protocol describes a randomized, controlled, assessor-blinded preclinical study designed to evaluate moxibustion in a disease-syndrome combination rat model of RA. Eligible rats will undergo exposure to a controlled wind-, cold-, and dampness-related environment followed by Complete Freund's Adjuvant (CFA) injection. After successful model induction has been confirmed using prespecified criteria, animals will be randomly allocated to a normal control group, an untreated model group, a heat-matched sham-moxibustion group, a Zusanli (ST36) moxibustion group, and a methotrexate active-comparator group. All animals will undergo standardized handling and restraint procedures. Moxibustion will be administered for 20 min once daily for 15 consecutive days, whereas methotrexate will be administered at the prespecified dose and frequency. The primary outcome will be the histopathological synovitis score. Secondary outcomes will include paw volume, arthritis index, joint structural damage, serum and synovial inflammatory mediators, and functional assessments. Autophagy will be evaluated using LC3-II/LC3-I, SQSTM1/p62, Beclin-1, and complementary assessments of autophagic flux. Ferroptosis-related outcomes will include GPX4, SLC7A11, ACSL4, lipid peroxidation, glutathione, reactive oxygen species, and tissue iron levels. Outcome assessment and statistical analysis will be performed by investigators blinded to group allocation. This study is expected to provide a reproducible framework for distinguishing the specific effects of moxibustion from non-specific heat, restraint, and handling effects, and to generate mechanistic evidence supporting subsequent translational and clinical investigations.
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ACS Applied Materials & Interfaces
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2026
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IF 7.8
Nannan Fu,Liyou Guo,Shili Zhou,Jinyang Wang,Zhixiong Zhan,Qiuhua Li,Jingyao Li,Jiaxuan Chen,Xiaoya Zhao,Ming Li,Yue Zheng,Dong-Yang Zhang
Utilizing nanotechnology to deliver multiple anticancer drugs holds the potential to enhance the anticancer effect. However, most drug carriers have limitations such as their own toxicity and low drug loading rate. Besides, depleting the excessive glutathione (GSH) in tumor cells not only induces ferroptosis in cancer cells but also has the potential to enhance photodynamic therapy. Inspired by previous work, hydroxyl groups were introduced into the ferroptosis inducer cinnamaldehyde to enhance its hydrogen bond interaction with the photosensitizer chlorins e6, thereby constructing stable self-assembled nanodrugs in solution and naming them TC. The prepared nanodrugs possess high drug loading capacity and acidic-responsive release properties, enabling efficient accumulation in tumor tissues. The TC not only consumes GSH through 3, 4, 5-trihydroxycinnamic aldehyde and down-regulate glutathione peroxidase 4, but also generates reactive oxygen species under irradiation, thereby increasing the level of lipid peroxidation and causing cancer cell apoptosis as well as ferroptosis. Additionally, the immunogenic cell death caused by combined therapy releases tumor-associated antigens, enhances antitumor immune responses, and inhibits tumor growth and metastasis in vivo and in vitro experiments, with no obvious toxicity. This study offers a unique molecular assembly modification strategy for the construction of self-assembled nanoplatforms to advance the field of carrier-free nanodrug.
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JOURNAL OF MEDICINAL CHEMISTRY
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2026
·
IF 7.3
Li-Juan Zhao,Rui Yu,Ying Liu,Jia-Yi Yin,Hang Jin,Jin-Gang Zhang,Cong-Jun Liu,Guo-Liang Lu,Yan Li,Ning Wang,Yi-Chao Zheng,Ya Gao,Kangdong Liu,Xing-Jie Dai
Abstract Lysine-specific demethylase 1 (KDM1A) is an FAD-dependent epigenetic target implicated in cancer progression. Starting from lead compound ZY-1 (IC50 = 105 nM), we designed a series of quinazoline-based reversible KDM1A inhibitors via a functional group migration strategy. Structure−activity relationship studies (SARs) identified JH-1 as the most potent analogue, with an IC50 of 35 nM. JH-1 selectively binds KDM1A, inhibits H3K4me1/2 demethylation, and induces both ferroptosis (lipid ROS accumulation) and apoptosis in esophageal cancer cells. In a KYSE510 xenograft model, oral administration of JH-1 significantly suppressed tumor growth without obvious toxicity. These results establish JH-1 as a promising reversible KDM1A inhibitor and validate the quinazoline scaffold for epigenetic cancer therapy.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Yuxi Huang,Wenyi Tang,Mei Xu,Liyun Luo,Tou Kun Chong,Qianglin Guan,Kaizhuang Huang,Kan Liu,Cunxue Pan,Jian Chen
Takotsubo syndrome (TTS), once considered benign, can cause life-threatening myocardial injury. Although oxidative stress and ferroptosis are implicated in its pathogenesis, targeted therapies are not available for TTS. We demonstrate that sulforaphane (SFN), a natural Nrf2 activator, mitigates TTS-related injury in isoproterenol-induced rat models and AC16 cardiomyocytes. Isoproterenol induced ferroptosis and oxidative stress by impairing Nrf2 signaling. SFN treatment restored myocardial structure and function while enhancing antioxidant capacity, reducing mitochondrial damage, and suppressing ferroptosis markers. Additionally, similar to Fer-1 (a ferroptosis inhibitor), SFN reduced intracellular ferrous levels but uniquely activated Nrf2-driven endogenous defenses. Notably, Nrf2 inhibition abrogated the benefits of SFN in both in vitro and in vivo experiments. These findings highlight SFN as a dual-action therapeutic for TTS, simultaneously targeting oxidative stress and ferroptosis via Nrf2 activation. The therapeutic efficacy of SFN, combined with endogenous pathway modulation, underscores its translational potential for improving TTS outcomes.
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JOURNAL OF NEUROIMMUNOLOGY
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2026
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IF 3.1
Guihua Wu,Fuwei Wang,Zihao Chen,Nan Zheng,Qiong Zhou,Lihua Xie,Xinyu Yang,Daibo Song,Qiang Sun,Jiantao Lin,Li Li
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that currently lacks efficacious therapeutic interventions. It's well documented that ferroptosis is extensively involved in the progression and pathogenesis of AD. Betaine, a critical nutrient for mammal health, is reported to possess neuroprotective actions. The objective of the current research was to investigate whether betaine could mitigate neuronal impairments by suppressing ferroptosis in SH-SY5Y neuroblastoma cells injured by glutamate. The results indicate that betaine improved the survival rate and reversed morphology changes of glutamate-damaged SH-SY5Y cells. Additionally, betaine reduced the intracellular accumulation of Fe 2+ , malondialdehyde (MDA), lipid reactive oxygen species (ROS), and lactate dehydrogenase (LDH) release induced by glutamate. And reversed the decreased glutathione (GSH) content and downregulation of ferroptosis inhibitor glutathione peroxidase 4 (GPX4) expression were observed upon betaine administration. Additionally, betaine facilitated the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus in SH-SY5Y cells induced by glutamate. Molecular docking validated high-affinity binding between betaine and Nrf2. Collectively, betaine could exert neuroprotective effects by alleviating ferroptosis via activation of the Nrf2 pathway, thereby positioning it as a potential candidate for targeting ferroptosis-driven neurodegeneration in AD.
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FISH PHYSIOLOGY AND BIOCHEMISTRY
·
2026
·Vol. 52
·期 2
·40
·
IF 3
Zhang Shasha,Li Xinran,Gao Yaxin,Dong Qian,Jin Xiaomin,Shi Pan,Dong Jingquan
Difenoconazole (DFZ) is a persistent triazole fungicide that leads to aquatic toxicity and ecosystem damage due to its environmental persistence and high toxicity. Curcumin (CUR), a natural polyphenol derived from turmeric, exhibits strong anti-inflammatory, antioxidant, and antitumor properties. This study assesses CUR’s protective role against DFZ-induced kidney injury in carp and investigates its mechanisms. Carp were exposed to DFZ for 30 days, with dietary supplementation of 400 mg/kg CUR. H&E staining revealed that CUR significantly reduced DFZ-induced histopathological damage in the kidneys. Dihydroethidium staining and biochemical assays demonstrated that CUR effectively lowered Reactive Oxygen Species levels and lipid peroxidation. Through biochemical kits, qPCR, and Western blotting, it was found that CUR decreased T-AOC and iron content, while activating the Nrf2/HO-1 pathway, thereby alleviating ferroptosis. CUR also upregulated the expression of xCT and GPX4, increased GSH levels, and further suppressed ferroptosis. In terms of inflammation, CUR improved the response by reducing pro-inflammatory cytokines (iNOS, IL-1β, IL-6, TNF-α) and increasing anti-inflammatory factors (IL-10, TGF-β1). With regard to apoptosis, CUR inhibited pro-apoptotic proteins (Bax, Cleaved-caspase3, Cleaved-caspase9, Cytochrome c) and restored the anti-apoptotic protein Bcl-2. In conclusion, CUR alleviates DFZ-induced kidney injury in carp by inhibiting ferroptosis through the Nrf2/GPX4 axis, while reducing oxidative stress, inflammation, and apoptosis. This study highlights CUR as a promising natural agent for mitigating environmental toxicity caused by triazole fungicides. Graphical
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ANALYTICAL AND BIOANALYTICAL CHEMISTRY
·
2026
·
IF 4.1
Tang Jinping,Qian Fuqiang,Wang Yuhai,Wang Chunxu,Kong Dewen
Ferroptosis is a novel form of programmed cell death distinct from apoptosis, necrosis, and autophagy, characterized by the abnormal accumulation of iron-dependent lipid peroxides. Increasing evidence suggests that ferroptosis is widely involved in various diseases, including neurodegenerative disorders, cancers, and cardiovascular diseases. However, the mechanisms of enzymes promoting lipid peroxidation remain poorly understood. The endoplasmic reticulum monooxygenase (MMO) mainly composed of cytochrome P450 (CYPs) and cytochrome P450 reductase (CPR) transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to molecular oxygen, leading to the generation of reactive radical intermediates and hydrogen peroxide. Subsequently, peroxidation of unsaturated liposomes disrupts membrane integrity and leads to ferroptosis. Herein, we elucidate the molecular details of MMO-liposome interactions and reveal their association with phospholipid membrane permeabilization in ferroptosis. Using Raman spectroscopy, we found that MMO interacted with unsaturated liposomes in the presence of electron donors, disrupting the conformation order of fatty acid chains. Furthermore, the degree of unsaturation in the liposomes positively correlates with the extent of peroxidation. Simultaneously, through the Raman spectra of the CYP 3A4 redox center, the relationship between MMO-liposome interactions and reactive oxygen species (ROS) generation is revealed, providing new insights into the mechanistic analysis of MMO-mediated ferroptosis. Moreover, the addition of Fe 3+ promotes the generation of reactive hydroxyl radicals, accelerating the extent of liposomal peroxidation. This study provides new mechanistic insights into how MMO promotes ferroptosis through lipid peroxidation and offers a theoretical basis for the development of novel anticancer therapeutic strategies. Graphical abstract
The alternative text for this image may have been generated using AI.
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
HaoranZhong,Lei Sun,Jiajun Yu,Yanrong Wang,Tongjie Xu,Tingfeng Yang,Niangkun Liu,Jiayuan Chen,Jinwu Liu,Haochen,Wenguang Fu
Liver regeneration is essential for recovery after major resection or acute injury, yet early regenerative failure remains common. Ferroptosis, an iron-dependent form of lipid peroxidation-driven cell death, impairs hepatocyte survival and may constrain regeneration. Naringenin (NAR), a citrus flavonoid with hepatoprotective activity, has been reported to modulate oxidative stress; however, whether it supports liver regeneration through ferroptosis modulation and which upstream targets are involved remains unclear. Here, hepatocyte models (AML12, Huh7, HepG2) and a murine 70% partial hepatectomy (PHx) model were used to investigate the involvement of PPARα signaling. Proliferation was assessed by CCK-8, EdU, and cell-cycle proteins. Ferroptosis-associated readouts (Fe 2+ , MDA, ROS, GSH) were measured following RSL3 exposure with or without NAR, ferrostatin-1, fenofibrate, or GW6471. Target identification involved network pharmacology, molecular docking, protease protection assay, and CETSA. In PHx mice, NAR was associated with improved liver regrowth (LW/BW ↑25% at 48 h), reduced ALT/AST (∼30–40%), increased proliferation markers, elevated GSH/CAT, and decreased Fe 2+ /MDA. In vitro, NAR increased GPX4/SLC7A11 expression and attenuated RSL3-induced ferroptosis-associated changes. These effects were mimicked by fenofibrate and attenuated by GW6471. NAR was associated with increased PPARα stability and expression. These findings suggest that NAR is associated with reduced ferroptosis and improved liver regeneration, potentially through modulation of PPARα-related signaling, warranting further validation.
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Cell Reports Medicine
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2026
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IF 14
Qiang Zhang,Yue Kong,Yinglin Long,Xue Li,Liang Wang,Zhanhao Luo,Xiaoya Yang,Yanchun Xie,Quanwei Yu,Jing Yu,Dayi Liang,Wenhao Yuan,Xiaomin Cheng,Yaqi Su,Kaisa Cui,Guobao Tian,Zhen He,Ping Lan
Immune evasion remains a major challenge in colorectal cancer (CRC) treatment. Here, we identify that druggable β-catenin palmitoylation at cysteine 466 (C466) by ZDHHC5 acts as a competitive switch, displacing S-nitrosylation and coordinating an immunosuppressive program. The palmitoylated state stabilizes the β-catenin/TCF4 complex, which simultaneously upregulates SLC7A11 to suppress immunogenic ferroptosis, critical for CD8 + T cell priming, and PD-L1 to inhibit cytotoxic CD8 + T cells, thereby impairing both the initiation and effector phases of anti-tumor immunity. Clinically, ZDHHC5 expression predicts poor survival and resistance to anti-PD-L1 therapy. Silencing ZDHHC5 reduced tumor growth in patient-derived organoids and xenografts, while Zdhhc5 ablation in mice inhibited CRC progression by reversing immunogenic ferroptosis suppression and alleviating PD-L1-mediated T cell inhibition. Importantly, β-cat-oxazole, a first-in-class inhibitor, disrupts ZDHHC5-β-catenin binding, thereby restoring immunogenic ferroptosis and blocking PD-L1-mediated immunosuppression, ultimately suppressing tumor growth. Our findings establish targeting of this palmitoyl-switch as a precision strategy to overcome therapeutic resistance.
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