BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2026
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IF 2.5
Hai Huang,Liwei Guo,Hansong Sun,Yunhong Liu,Jun Zhang,Weijie Tang,Xiaodong Xia,Yu Wang,Ni Chen,Dong Lv,Jing Yang
Objective To investigate the mechanism of action of saikosaponin D (SSD) on bladder cancer (BCa) and evaluate its synergistic antitumor efficacy with the chemotherapeutic agent gemcitabine (GEM). Methods MTT, colony formation, Transwell, and scratch wound healing assays detected SSD's effects on the proliferation, invasion, and migration of RT112 and T24 cells. Specific inhibitors identified cell death mode. Western blotting, immunohistochemistry, and flow cytometry verified ferroptosis-related protein expression and oxidative stress. Network pharmacology predicted core pathways, validated by examining PI3K/AKT pathway activity. Animal models evaluated the synergistic effect of SSD and GEM. Results In vitro, SSD dose-dependently inhibited the BCa cells proliferation, invasion, and migration, and upregulating E-cadherin whilst downregulating N-cadherin, Vimentin, and Snail. The effects were blocked by the ferroptosis inhibitor Fer-1. Network pharmacology identified the PI3K/AKT pathway as a core target. Moreover, SSD regulated the GPX4/SLC7A11/ACSL4, suppressed PI3K/AKT phosphorylation, and triggered lipid peroxidation and reactive oxygen species accumulation, partially reversed by a PI3K-specific phosphopeptide agonist. In vivo, SSD inhibited tumor growth, and its combination with GEM showed superior efficacy. The combination therapy most effectively downregulated SLC7A11, GPX4, Vimentin, N-cadherin and Snail, while upregulating the ACSL4 and E-cadherin. Conclusion SSD inhibits the malignant phenotype of BCa by targeting PI3K/AKT to trigger ferroptosis. Its synergistic effect with GEM from the dual mechanisms of ferroptosis sensitization and epithelial-mesenchymal transition inhibition, providing an innovative combination strategy based on natural product active ingredients to overcome bladder cancer chemoresistance.
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Advanced Science
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2026
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IF 14.1
Tingting Zhang,Mengyi Xu,Yan Zhang,Zhiwen Li,Danqing Song,Jing Pang,Ke Li,Yanxiang Wang
Bacterial-based materials, leveraging their inherent hypoxia and immunosuppressive microenvironment-targeting capabilities, immunomodulatory effects, and drug delivery advantages, have emerged as promising strategies to modulate the tumor microenvironment (TME) for converting immunologically “cold” tumors into “hot” ones. This study innovatively functionalizes Lactobacillus reuteri ( L. reuteri ) using metal-phenolic networks (MPNs) to co-deliver αPD-L1 antibodies and gallium ions (Ga 3 + ) for synergistic anti-tumor therapy. The MPN coating materials enable pH-responsive drug release, whereby αPD-L1 reverses immunosuppression and Ga 3 + disrupts tumor iron metabolism, mimicking Fe 3 + to induce selective ferroptosis. In vivo evaluations in B16 and LLC tumor-bearing mouse models revealed that functionalized L. reuteri had the potential to reprogram the tumor immune microenvironment and significantly enhanced tumor regression. This system achieved multifunctional tumor regression in vivo, integrating bacterial hypoxia-driven chemotaxis, MPN-mediated ferroptosis, and immune checkpoint inhibitors (ICIs)-driven immune activation. Thus, the multifunctional materials offer a novel strategy for treating refractory or immunologically “cold” tumors.
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ENVIRONMENTAL POLLUTION
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2026
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IF 7.2
Zixu Li,Muge Xu,Yahan Zhang,Yao Chen,Weiwei Feng,Ting Zhao,Liuqing Yang,Guanghua Mao,Xiangyang Wu
The widespread presence of plastic pollutants, particularly phthalate esters such as dibutyl phthalate (DBP), poses a significant threat to both ecosystems and human health. Despite the accumulating evidence of DBP toxicity, the mechanisms driving DBP-induced hepatotoxicity remain poorly understood. In this study, an integrated approach combining network toxicology, molecular docking, and multidimensional experimental validation was applied to elucidate the molecular pathways through which DBP causes liver damage. Ferroptosis was identified as a central player in DBP-induced hepatotoxicity. The results showed that DBP activates the aryl hydrocarbon receptor (AhR), regulating the NRF2/HO-1 signaling axis, which in turn induces iron overload and lipid peroxidation. Furthermore, ferroptotic hepatocytes release high-mobility group box 1 (HMGB1), activating the TLR4/NF-κB pathway in macrophages and amplifying inflammatory responses that exacerbate liver injury. Crucially, inhibition of either AhR expression or ferroptosis significantly attenuated these changes, highlighting the potential of AhR and ferroptosis as therapeutic targets. Together, these findings establish a novel mechanistic framework for DBP-induced hepatotoxicity: the AhR–NRF2/HO-1–ferroptosis–HMGB1/TLR4 axis. This study advances our understanding of plasticizer toxicity and offers insights for risk assessment and intervention strategies for combating environmental hepatotoxins.
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CHEMICO-BIOLOGICAL INTERACTIONS
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2026
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IF 5.2
Jiaqi Li,Zhengxin Lu,Nan Zhang,Xiaowei Zhou,Yuanbiao Ma,Jia-qi Li,Yimu Zhang,Zhewen Deng,Na Lin,Peng Yue,Yilin Yang,Qi Zhang,Bo Ma
Andrographolide (Andro), the primary bioactive compound of Andrographis paniculata , has known bioactivities but also male reproductive toxicity with unclear mechanisms. This study investigated its testicular injury effects and mechanism, focusing on Sertoli cells (SCs) ferroptosis. Toxicity was evaluated in mice and SCs. Mechanisms were probed using RT-qPCR, Western blot, co-immunoprecipitation, and ubiquitination assays. LC-MS/MS assessed tissue distribution. Molecular docking and dynamics simulations characterized the Andro-β-TrCP interaction. The results demonstrated that Andro exposure caused significant testicular atrophy, blood-testis barrier (BTB) disruption, and spermatogenic impairment in mice. Meanwhile, pharmacokinetic analysis revealed SCs as the primary target of Andro-induced testicular damage, showing rapid Andro accumulation that was subsequently detected in sperm and the epididymis. Furthermore, Andro triggered ferroptosis in testicular injury and SCs, marked by increased ROS, MDA, iron overload, and lipid peroxidation. These effects were rescued by the ferroptosis inhibitor deferoxamine. Mechanistically, Andro directly bound to β-TrCP, downregulating its expression and subsequently stabilizing ATF4 by impairing its ubiquitin-mediated degradation. Silencing ATF4 inhibited ferroptosis and restored cell viability upon Andro challenge. The direct Andro-β-TrCP interaction was consistently confirmed by molecular docking, dynamics simulations, and CETSA. This study reveals that Andro triggers SCs ferroptosis by inhibiting β-TrCP-mediated ATF4 ubiquitination and degradation, leading to BTB disruption and spermatogenic impairment. These findings provide a theoretical basis for optimizing clinical application of Andro in the future.
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Acta Biomaterialia
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2026
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IF 10.4
Yu Liu,Ziwen Xiao,Yu Zhang,Qian Chen,Siyu Luo,Yaoqing Wang,Zhaohua Miao,Zhenchao Tao,Deyan Gong
Acute liver failure (ALF) can result from the progressive development of acute liver injury triggered by acetaminophen (APAP) overdose. The core mechanisms involve an imbalance in the antioxidant system and upregulation of the inflammatory response, which collectively induce ferroptosis/apoptosis. Herein, nanozymes (PPy-Mg NPs) were synthesized through coordination reaction between polypyrrole nanoparticles (PPy NPs) and magnesium ions. The enriched PPy-Mg NPs were explored as active anti-inflammatory nanozymes for effective acute liver injury treatment. Enriched cationic PPy-Mg NPs in the liver effectively scavenged excess reactive oxygen and nitrogen species (RONS) and cell-free DNA. It is worth emphasizing that in the delayed AILI mouse models, bioactive PPy-Mg NPs not only reduced oxidative stress levels but also modulated multiple biological signaling pathways, such as NF-κB, Nrf2-Keap1, ferroptosis/apoptosis. The research indicates the possible medical application of PPy-Mg NPs nanozymes in efficient enrichment treatment for acute liver injury. Statement of Significance APAP-induced liver injury (AILI) can progress to acute liver failure (ALF), presenting a significant clinical challenge. Currently, N-acetylcysteine (NAC) is the only medication approved treatment; however, its efficacy in patients with advanced AILI remains unsatisfactory. Therefore, the development of new therapeutics for the treatment of AILI are crucial. This work developed a PPy-Mg NPs nanozyme for the efficient AILI treatment. PPy-Mg NPs provide constructive applications of polypyrrole-based nanozymes for AILI treatment, which covers upstream metabolic rescue (RONS scavenging), necrotic debris clearance (cfDNA removal), and residual cell protection (ferroptosis inhibition) across temporal and spatial dimensions, holds potential for extending therapeutic windows and enhancing protection rates in high-risk/complex cases.
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FREE RADICAL BIOLOGY AND MEDICINE
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2026
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IF 8
Shenghui Zhang,Qin Liu,Bo Chen,Hui Chang,Ying Pan,Yanli Liu,Xin Zhao,Juntang Lin
MenSC-EVs alleviate STZ-induced ovarian dysfunction in diabetic mice. • MenSC-EVs suppress high-glucose-induced ferroptosis in granulosa cells. • EV-associated HSPA5 mediates protection via AKT/mTOR–BECN1/SLC7A11 signaling. Type 1 diabetes mellitus (T1DM) is associated with ovarian dysfunction, including menstrual irregularities, impaired ovarian reserve, and premature reproductive aging, yet effective therapeutic strategies to safeguard ovarian function against metabolic stress remain limited. Mesenchymal stem cells (MSCs) have emerged as pivotal regulators of tissue homeostasis, with their paracrine effects largely mediated by extracellular vesicles (EVs). Here, we demonstrate that menstrual blood-derived endometrial stem cell-EVs (MenSC-EVs) alleviate streptozotocin (STZ)-induced ovarian dysfunction and inhibit granulosa cells (GCs) ferroptosis by delivering HSPA5. Mechanistically, EV-associated HSPA5 restored AKT/mTOR signaling and was accompanied by reduced BECN1 phosphorylation, thereby preserving the SLC7A11/GPX4-associated antioxidant pathway. We further show that BECN1 directly interacts with SLC7A11, linking BECN1 signaling to regulation of the system Xc−/GPX4 antioxidant axis. MenSC-EVs preserved this antioxidant pathway and reduced lipid peroxidation in injured GCs. Collectively, these findings identify an HSPA5-dependent anti-ferroptotic mechanism through which MenSC-EVs ameliorate T1DM-associated ovarian dysfunction, supporting their potential as an ovarian-protective strategy under diabetic conditions. Download: Download high-res image (241KB) Download: Download full-size image
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Chinese Medicine
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2025
·Vol. 20
·期 1
·1-18
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IF 5.7
Qiu Yuping,Li Shupei,Jiang Mingzuo,Huang Ang,Yang Ya,Chen Xi,Li Hui,Yang Zhizhou,Wei Juan,Xuan Ji
Background Lang Qing A Ta (Huagan Tongluo Fang, HGTLF) is a Tibetan medicine with significant anti-liver fibrosis effects and good efficacy in the treatment of liver diseases, including non-alcoholic fatty liver disease (NAFLD). Quercetagetin (QG) has been identified as an active ingredient of HGTLF that is absorbed into the blood. This study aims to investigate the role of QG in the anti-liver fibrosis effect of HGTLF in NAFLD. Methods CCl 4 injection-induced liver fibrosis and high-fat, high-cholesterol diet-induced non-alcoholic steatohepatitis (NASH) mouse models were established. Transforming growth factor-β1 (TGF-β1)-induced hepatic stellate cells (HSCs) were used as in vitro models. The effect of QG on the stability and degradation pathway of glu-tathione peroxidase 4 (GPX4) protein was investigated. Results QG improved liver function and hyperlipidemia in CCl 4 -injected mice and NASH mice, and alleviated hepatic lipid deposition and hepatic fibrosis. TGF-β1 treatment promoted the expression of α-smooth muscle actin and fibrosis-related genes, while QG reversed this phenomenon and inhibited HSC activation. QG increased the intracellular labile iron pool and lipid reactive oxygen species in HSCs. Treatment with the ferroptosis inhibitor ferrostatin-1 reversed the inhibitory effect of QG on TGF-β1-induced HSC activation. QG reduced GPX4 protein stability and regulated GPX4 K167 ubiquitination via the membrane-associated ring-CH-type finger 8 (MARCHF8)-mediated ubiquitin–proteasome pathway. Interference with MARCHF8 attenuated the effect of QG and promoted HSC activation induced by TGF-β1. Conclusion QG, the active ingredient of HGTLF, can induce ferroptosis of HSCs by targeting the degradation of GPX4 through ubiquitination and inhibit HSC activation, thereby alleviating liver fibrosis in NAFLD.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2025
·Vol. 26
·期 5
·2027
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IF 4.9
Shuangliu Chen,Jiřimutu Xiao,Shijie Zhou,Taxi Wumiti,Zitong Zhao,Ruihua Zhao,Yalan Pan,Qing Wang,Yong Ma,Lan Wu,Yang Guo
Dysregulated iron metabolism-induced ferroptosis is considered a key pathological mechanism in the development of osteoporosis (OP). G protein-coupled receptor 30 (GPR30, also known as Gper1) is an estrogen-binding receptor that has shown therapeutic benefits in patients with certain degenerative diseases. Moreover, several studies have demonstrated the anti-ferroptotic effects of estrogen receptor activation. However, its role in the prevention and treatment of OP remains unclear, and there are currently no reports on the anti-ferroptotic function of GPR30 in OP. Therefore, this study aimed to investigate the ferroptosis-related effects and mechanisms of GPR30 in the context of OP. In vivo and in vitro experiments were conducted using wild-type (WT)C57BL/6female mice and GPR30-knockout (GPR30-KO)C57BL/6Jfemale mice. The microarchitecture of the distal femur was assessed using micro-computed tomography (micro-CT), and histomorphological changes were analyzed via hematoxylin and eosin (H&E) staining. Bone marrow mesenchymal stem cells (BMSCs) were isolated and cultured to establish an iron overload model using ferric ammonium citrate (FAC). Interventions included GPR30 overexpression via transfection and BMP-6 inhibition using LDN-214117. Cell viability was evaluated with the CCK-8 assay, while osteogenic differentiation and mineralization levels were assessed using ALP and Alizarin Red S (ARS) staining. Iron accumulation was detected via Prussian blue staining, oxidative stress levels were evaluated using ROS staining, and mitochondrial membrane potential changes were analyzed using JC-1 staining. Transmission electron microscopy (TEM) was employed to observe mitochondrial ultrastructural changes. Additionally, key gene and protein expression levels were measured using immunofluorescence and Western blotting. The micro-CT analysis revealed significant bone microarchitecture deterioration and bone loss in the GPR30-KO mouse model. At the cellular level, GPR30 overexpression markedly reduced iron accumulation and oxidative stress in BMSCs, restored the mitochondrial membrane potential, and improved the mitochondrial ultrastructure. Furthermore, GPR30 enhanced osteogenic differentiation in BMSCs by promoting the activation of the BMP-6/HEP/FPN signaling pathway, leading to increased expression of osteogenic markers. The protective effects of GPR30 were reversed by the BMP-6 inhibitor LDN-214117, indicating that BMP-6 is a critical mediator in GPR30-regulated iron metabolism and ferroptosis inhibition. GPR30 inhibits ferroptosis in BMSCs and enhances osteogenic differentiation by activating the BMP-6/HEP/FPN signaling pathway. This provides new insights and potential therapeutic targets for the treatment of osteoporosis OP.
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MOLECULAR MEDICINE
·
2025
·Vol. 31
·期 1
·1-23
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IF 6.4
Wang Qiuhong,Wei Dong,Li Chunman,Yang Xiawei,Su Kun,Wang Tao,Zou Renchao,Wang Lianmin,Cun Dongyun,Tang Bo,Wu Tao
Section
Background
Pancreatic cancer is highly lethal, and METTL3 plays a crucial role in the regulation of m6A. However, the therapeutic potential of METTL3 in pancreatic cancer is unclear.
Section
Methods
By means of functional gain and loss experiments, the relationship between METTL3 and gemcitabine resistance as well as ferroptosis was explored. The target genes of METTL3 were screened, and the influence of O-GlcNAcylation on the stability and ubiquitination modification of METTL3 was dissected.
Section
Results
We found that METTL3 is highly expressed in pancreatic cancer and regulates ferroptosis and gemcitabine resistance by promoting the degradation of HMGB1 in an m6A-YTHDF2-dependent manner. O-GlcNAcylation modulates the METTL3’s stability. The interaction between the deubiquitinase EIF3H and METTL3 is influenced by O-GlcNAcylation.
Section
Conclusion
METTL3 affects pancreatic cancer progression by promoting degradation of HMGB1. The O-GlcNAcylation of METTL3 not only stabilizes METTL3 but also augments EIF3H-mediated deubiquitination. These findings uncover potential mechanisms underlying gemcitabine resistance in pancreatic cancer and offer potential therapeutic strategies for the treatment of this disease.
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MOLECULAR PHARMACEUTICS
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2025
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IF 4.5
Jieming Zhang,Fangfang Zhou,Xin Du,Meiru Zhang,Suxiao Li,Songtao Niu,Qungang Chang,Yongju He
Cisplatin-based chemotherapy is widely used to combat cancers through an apoptosis pathway. However, drug resistance induced by upregulated glutathione (GSH) in tumor cells and systemic side effects significantly compromise its therapeutic efficacy. The application of nanocarriers with a GSH-scavenging ability is a promising strategy to overcome these obstacles. In addition, ferroptosis has shown great potential in eliminating the limitation of apoptosis-mediated chemotherapeutics. Herein, a multifunctional nanoplatform (S4MON-Cis@TA-Fe3+), loaded with cisplatin in tetrasulfide bonds-bridged mesoporous organosilica nanoparticles (S4MON) and then coated with tannic acid (TA)-Fe3+ metal-phenolic network, is developed for apoptosis–ferroptosis synergistic therapy. In the acidic tumor cells, the outer TA-Fe3+ network is disassembled into Fe3+ and TA, and the internal S4MON-Cis network is exposed. The released TA and endogenous GSH reduce Fe3+ to Fe2+, which significantly increases cellular oxidative stress through the Fenton reaction and GSH consumption. Moreover, S4MON-Cis decreases the intracellular GSH content through redox reaction between tetrasulfide bonds and GSH, which further augments cellular oxidative stress and triggers nanoparticle degradation to release cisplatin. Subsequently, cisplatin induces apoptosis and elevates the cellular hydrogen peroxide level to improve the Fenton reaction efficiency. The multiple oxidative stress amplification greatly promotes lipid peroxidation and glutathione peroxidase 4 downregulation, boosting tumor ferroptosis. Meanwhile, the dual GSH elimination significantly improves the antitumor effect of cisplatin. As a result, S4MON-Cis@TA-Fe3+ exhibits effective tumor growth inhibition through self-enhanced apoptosis–ferroptosis synergistic therapy, which holds great promise for cancer therapy.
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Small
·
2026
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IF 11.8
Chunrong Ren,Ruxi Deng,Jiameng Ding,Wuyang Wei,Hai Wang,Ying Liu,Li Ding,Meiqi Chang,Yu Chen,Yang Zhou
Hepatocellular carcinoma, a malignant tumor with high incidence and mortality rates, urgently requires the development of novel therapeutic strategies that are highly efficient and minimally toxic. Sonodynamic therapy has garnered significant attention due to its non-invasiveness, deep tissue penetration capability, and low side effects, yet its efficacy is highly dependent on the development of high-performance sonocatalyst. This study successfully prepared Pd-integrated indium oxide with abundant structural defects as a novel sonocatalyst for the highly efficient sonocatalytic eradication of hepatocellular carcinoma. Furthermore, Pd confers catalase-like and peroxidase-like enzymatic activities, modulating the tumor microenvironment to alleviate hypoxia and augment hydroxyl radical production, consequently amplifying sonocatalytic efficacy. Mechanistic insights identify a synergistic pathway involving both apoptosis and ferroptosis. This hybridized apoptotic/ferroptotic pathway acts synergistically to amplify oxidative cellular damage, ultimately achieving significant suppression and eradication of hepatocellular carcinoma. This work not only provides a novel strategy for designing efficient sonosensitizers through defect engineering but also unveils a new mechanism whereby engineered sonocatalysts can treat cancer by triggering hybridized cell death pathways, offering a promising approach and theoretical foundation for the sonodynamic therapy of liver cancer.
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Redox Biology
·
2026
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IF 16.2
Zitong Zhao,Ge Ge,Menghan Gong,Yi Liu,Liying Ma,Dongdong Zhang,Li Sun,Yongmei Song
Background Cisplatin resistance is a primary cause of treatment failure in ovarian cancer (OC), partly due to enhanced antioxidant defenses that counteract cisplatin-induced DNA damage and reactive oxygen species (ROS). Beyond the classic Glutathione Peroxidase 4 (GPX4) pathway, evidence suggests that non-canonical pathways like those mediated by Ferroptosis Suppressor Protein 1 (FSP1) may drive resistance. This study aims to elucidate how such alternative pathways facilitate resistance under cisplatin-induced ROS stress. Methods Ubiquitin Specific Peptidase 18 (USP18) was identified from a deubiquitination library. Protein/RNA interaction and m 6 A analyses revealed its regulation of downstream effectors Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and FSP1. The combination of cisplatin with the FSP1 inhibitor (iFSP1) was evaluated in vitro and in vivo models. Results Cisplatin-induced ROS upregulates the expression of the USP18 through the transcription factor c-JUN, establishing the ROS-c-JUN-USP18 signaling axis. This axis stabilizes the IGF2BP2 protein via USP18-mediated deubiquitination, which in turn enhances the stability of FSP1 mRNA in an m6A methylation-dependent manner, thereby driving the selective activation of the FSP1-mediated pathway over the canonical GPX4 pathway. The predictive efficacy of models derived from the ROS-c-JUN-USP18-IGF2BP2-FSP1 axis was demonstrated by ROC curves and nomograms, confirming their utility in identifying patients with cisplatin-resistant OC. Importantly, the combination of iFSP1 with cisplatin produces a significant synergistic effect, effectively overcoming drug resistance in USP18-high tumors. Conclusion This study elucidates the mechanism by which the ROS-c-JUN-USP18-IGF2BP2-FSP1 axis regulates cisplatin resistance and proposes a novel iFSP1-cisplatin combination therapy, offering a promising new strategy for OC treatment.
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