Materials Today
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2025
·
IF 22
Ying-Tao Zhong,Zi-Wen Qiu,Ke-Yan Zhang,Zhen-Ming Lu,Zhuo-Feng Li,Jun-Mei Nie,Yi Cen,Hong Cheng,Shi-Ying Li,Xiaoyuan Chen
Pyroptosis-inducing chemotherapeutics hold promise for activating both adaptive and innate immunity in breast cancer immunotherapy. However, their practical efficacy is often limited by inadequate expression of pyroptosis-executed gasdermin and insufficient transfer of tumor-derived DNA. In this work, our findings indicated that the epigenetic drug of decitabine (DEC) can increase the gasdermin E (GSDME) level in breast cancer cells, while the DNA-damaging chemotherapeutic drug of 7-ethyl-10-hydroxycamptothecin (SN38) can activate caspase-3 and cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway. Based on these discoveries, a glutathione (GSH)-responsive nanoplatform equipped with PD-L1 blockade peptide (PD-L1 pep) is further fabricated for targeting delivery of these chemotherapeutic combination to breast cancer cells. Interestingly, the apoptosis-pyroptosis switch (denoted as PL@SD) not only enables the cascade activation of caspase-3 and GSDME to induce an apoptosis-pyroptosis transition, but also accelerates the release of tumor-derived DNA through the pore-formation to elicit the cGAS-STING activity. Concurrently, PL@SD elevates dendritic cell maturation, cytotoxic T lymphocyte infiltration, natural killer cell recruitment and long-term immunological memory effect to boost adaptive and innate immunity, thus synergistically suppressing primary breast cancer, distant lung metastases and tumor rechallenge. Overall, this study presents an elaborate strategy for apoptosis-pyroptosis transition and cGAS-STING activation, which might provide a new insight to expand the applications of the existing therapeutic drugs for tumor immunotherapy.
研究领域:
肿瘤学
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免疫学
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药理学
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分子生物学
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DOI
高影响因子
Communications Biology
·
2025
·
IF 5.1
Wang Shanshan,Wu Zankai,Song Wenqin,Zhang Hui,Bu Xueshan,Gao Wenwei,Wu Kefan,Xia Zhongyuan,Zhao Bo,Wang Wei
Activation of the cGAS-STING pathway has been proposed as a potential pathogenic mechanism underlying postoperative cognitive dysfuncton (POCD). Analysis of public transcriptomic data from the hippocampus of male mice suggests upregulation of Rbm47 in an experimental POCD model. In vitro, knockdown (KD) of Rbm47 in BV2 cells reduces levels of cGAS, STING, TNF-α, IL-6, and IFN-β under isoflurane and lipopolysaccharide (Iso + LPS) conditions. HT22 cells exposed to culture medium from Rbm47 -KD BV2 cells treated with Iso + LPS show increased levels of MEF2C, GPX4, GSH, and SOD, and reduced levels of MDA and iron. Microglial Rbm47 overexpression amplifies cGAS-STING signaling and aggravates neuronal ferroptosis, which is reversed by the cGAS inhibitor RU.521. Rbm47 KD combined with RU.521 treatment synergistically ameliorates POCD in male mice. Mechanistically, the RRM2 domain of RBM47 interacts with the 3’UTR of cGAS mRNA, enhancing its stability. RUNX1 directly binds to the Rbm47 promoter and facilitates its transcription. RUNX1 overexpression activates the RBM47-cGAS-STING axis and exacerbates neuronal ferroptosis. Conversely, RUNX1 ablation ameliorates POCD, dampens the cGAS-STING signaling, and inhibits ferroptosis, which is abolished by RBM47 depletion. Our findings suggest that repression of RUNX1/RBM47 may represent a promising therapeutic strategy for POCD.
研究领域:
神经科学
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分子生物学
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免疫学
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细胞生物学
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麻醉与围术期医学
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DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2026
·Vol. 11
·期 1
·80
·
IF 81.2
Mu Min,Li Hui,Chen Bo,Fan Rangrang,Zhong Kunhong,Wang Guoqing,Feng Chenqian,Chen Nianyong,Guo Gang,Tong Aiping,Zou Bingwen
The broader clinical application of Bispecific T-cell engagers (BiTEs) is hindered by their short half-life, on-target off-tumor toxicity, and limited therapeutic effect for solid tumors. Herein, we constructed a bimetallic-enriched triple-kill nanobomb manganese/Co 2+ -dopamine@BiTE/HPT (MnO 2 /Co-DA@BiTE/HPT) based on metal-polyphenol to improve the immunosuppressive tumor microenvironment by activating innate and adaptive immunity, thereby enhancing the treatment efficacy of BiTEs (PD-L1/CD3). A hyaluronic acid-modified PD-L1 aptamer (HPT) was introduced to improve the active targeting of the nanobombs and bind with PD-L1 overexpressing colorectal cancer. Bimetallic (Mn 2+ /Co 2+ ) activated the STING pathway; simultaneously, photothermal therapy (PTT) induces DNA fragmentation to cooperate with bimetallic to amplify the STING signal to “heat” the “cold” tumor microenvironment. The “hot” tumor with a large amount of T-cell infiltration facilitated BiTE recruitment of T cells to kill tumor cells. Furthermore, the efficient therapeutic potency of the triple-kill nanobombs (STING, BiTE, and PTT) was determined in subcutaneous colorectal cancer, distal, lung metastasis, and postoperative recurrence models, which indicated that MnO 2 /Co-DA@BiTE/HPT could improve the immune microenvironment, produce long-term immune memory, inhibit tumor growth, and prevent tumor recurrence and metastasis.
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DOI
PubMed
高影响因子
Chinese Journal of Natural Medicines
·
2026
·Vol. 24
·期 7
·832-848
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IF 7.5
Jueyao Zou,Tongyao Hu,Zhengyu Zhang,Yong He,Yuxin Wang,Yixiao Zhou,Ziyan Zhu,Suyun Yu,Wei Zou,Zhonghong Wei,Yang Zhao,Yanhong Pan,Wenxing Chen,Yin Lu
Psoriasis is a chronic skin disease driven by skin inflammation and abnormal subcutaneous blood vessels. Yinxie Granules (YXKL) is a clinically effective traditional Chinese medicine (TCM) formula that has shown promise in psoriasis treatment, but its pharmacological mechanisms and material basis remain unclear, limiting its clinical application and co-administration with other drugs. In this study, we explored the mechanism and active components of YXKL in the treatment of psoriasis using patient samples, IMQ-induced psoriatic mice, zebrafish, and in vitro assays. We discovered that YXKL alleviated skin inflammation and restored the skin barrier by reducing M1 macrophage/Th17 infiltration, lowering pro-inflammatory cytokines (IL-6, IFN-β, IL-23, IL-17), and increasing loricrin expression. Mechanistically, we identified a dynamic transition in STING signaling during psoriasis progression. Both the STING/IRF3 and STING/NF-κB pathways were activated in moderate psoriasis, while only the STING/NF-κB pathway was hyperactivated in severe disease. YXKL specifically targeted the STING/NF-κB pathway to mitigate inflammation and vasculopathy but had no significant impact on the upstream regulators, including TRAF6, LKB1, AMPK, and ULK1. Quercetin and kaempferol were identified as the primary STING-modulating components in YXKL, binding to STING proteins and inhibiting downstream pathway activation. These flavonoid components mediate the anti-psoriatic effects of YXKL by simultaneously suppressing skin inflammation and angiogenesis while enhancing vascular integrity through STING inhibition in both keratinocytes and endothelial cells. Our results elucidated the molecular basis of YXKL for psoriasis treatment, highlighting STING/NF-κB as a pivotal therapeutic target in mitigating psoriasis development and providing natural candidate compounds as potential STING inhibitors.
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DOI
高影响因子
International Journal of Biological Sciences
·
2026
·Vol. 22
·期 7
·3886-3908
·
IF 11.7
Cai Yuchen,Zhou Tianyi,Sun Jiaming,Cai Xueyao,Shi Wenjun,Chen Junzhao,Zouboulis Christos C.,Sun Hao,Fu Yao,Chen Liangbo
Dysregulated lipid metabolism and chronic inflammation are hallmarks of aging, yet their interplay in age-related tissue disorders remains poorly defined. In the ocular surface, age-related meibomian gland dysfunction (ARMGD) is highly prevalent but mechanistically unclear, leading to significant visual impairment without targeted therapies. To identify key molecular drivers of ARMGD, we performed integrated multi-omics screening of aging mouse meibomian glands (MGs) and identified DHCR24, a key cholesterol metabolism enzyme, as a critical regulator of gland homeostasis. Single-cell sequencing identified age-associated downregulation of Dhcr24 predominantly in meibocytes. Based on this finding, we generated a meibocyte-specific Dhcr24 knockout (cKO) model, which exhibited typical ARMGD pathology including glandular atrophy, disrupted lipid homeostasis, and inflammatory activation. Further in vitro studies using SZ95 sebocytes demonstrated that DHCR24 deficiency induces mitochondrial dysfunction and cytosolic mitochondrial DNA (mtDNA) leakage, triggering cGAS/STING-dependent inflammatory senescence. Notably, AAV-mediated restoration of DHCR24 in mice reversed age-related gland pathology. Our findings establish DHCR24 as a dual-target regulator that maintains cholesterol metabolic homeostasis while suppressing mtDNA-driven inflammation via the cGAS-STING pathway, highlighting its therapeutic potential for ARMGD and related disorders characterized by lipid-inflammatory imbalance.
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Xintao Gao,Yulan Yin,Shuai Liu,Kehong Dong,Jing Wang,Chuanlong Guo
Fucoidan (FU) is a natural polymer from marine organisms, which has been widely studied and applied in drug delivery. In this study, FU nanoparticles loaded with proanthocyanidins (PCs) (FU/PCs NPs) were prepared and their effect and mechanism in protecting cisplatin-induced acute kidney injury (AKI) were studied. The in vitro studies confirmed that FU/PCs NPs increased the antioxidant activity of free PCs and protected the death of human kidney proximal tubule (HK-2) cells induced by cisplatin. Further mechanism studies showed that FU/PCs NPs protected the mitochondrial damage induced by cisplatin, activated mitophagy, inhibited the release of mitochondrial DNA (mtDNA), and inhibited the cGAS/STING signal pathway. The in vivo results also indicated that FU/PCs NPs protected cisplatin-induced AKI, including inhibiting the increase of blood urea nitrogen (BUN) and serum creatinine (SCr) levels induced by cisplatin. The mechanism studies confirmed that cisplatin induced an increase in the expression of mitophagy-related protein Pink/Pakrin, mitochondrial mtDNA release and cGAS/STING expression in mice kidney tissues. Pre-administration of FU/PCs NPs further activated mitophagy, as well as inhibiting mtDNA release and cGAS/STING expression. In conclusion, our research proved the role of mitophagy-mtDNA-cGAS/STING signal was involved in cisplatin-induced AKI.
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DOI
PubMed
高影响因子
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH
·
2025
·
IF 1.8
Jiaojiao Ren,Jun Ying,Haijian Liu,Shanshan Hu,Jiangdong Li,Danfei Zhou
Background: This study was designed to explore the action mechanism of stimulator of interferon genes (STING) on the differentiation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment of lung cancer.Methods: Bioinformatics analysis yielded a potential pathway for STING to regulate MDSC differentiation, the interferon regulatory factor 3 (IRF3)/NF-κB axis. The transfection efficiency of STING overexpression plasmid and small interfering RNA against IRF3 (siIRF3) was examined by quantitative real-time polymerase chain reaction (qRT-PCR). After transfection, A9 cells were co-cultured with extracted bone marrow cells (BMCs). MDSC differentiation, protein expression of the IRF3/NF-κB pathway, and changes in nuclear translocation of NF-κB were analyzed by flow cytometry, Western blot, and immunofluorescence staining experiments. A transplanted tumor mouse model was used for in vivo experiments. After cyclic diadenyl monophosphate (CDA; STING agonist) treatment, changes in MDSC differentiation and protein expression of the IRF3/NF-κB axis in transplanted tumors were verified by immunohistochemical staining, qRT-PCR, and Western blot.Results: Coculture of A9 cells and BMCs promoted MDSC differentiation, inhibited activation of IRF3/NF-κB signal in A9 cells, and boosted nuclear translocation of NF-κB. However, after the upregulation of STING, IRF3/NF-κB signal was activated, while MDSC differentiation and nuclear translocation of NF-κB were inhibited. SiIRF3 reversed the effects of STING overexpression. In vivo, CDA dampened MDSC differentiation and promoted protein expression of the IRF3/NF-κB axis.Conclusion: STING signal in lung cancer cells inhibits MDSC differentiation through activation of the IRF3/NF-κB pathway.
研究领域:
肿瘤学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2024
·
IF 5.4
Tao Jiang,Feikai Zhu,Xintao Gao,Xiaochen Wu,Wenyong Zhu,Chuanlong Guo
Acute kidney injury (AKI) is a common clinical problem with no effective treatment. Excessive folic acid (FA) induced kidney tubular injury is characterized by oxidative stress and inflammation, and is a common model of AKI. The excellent pharmacological activity of naringenin (NAR) makes it a potential agent for treating AKI, but its poor solubility limits its application. This study prepared NAR loaded nanoparticles (FU/PVP-NAR) using fucoidan (FU) and polyvinylpyrrolidone (PVP) as carriers, with a particle size of 23.96 ± 2.77 nm. In vitro studies showed that FU/PVP-NAR inhibited excessive FA induced proliferation inhibition, accumulation of reactive oxygen species (ROS), and disruption of mitochondrial membrane potential (MMP) of HK-2 cells. Further confirmed that FU/PVP-NAR inhibited FA induced DNA damage and Cyclic GMP–AMP synthase (cGAS)-stimulator of interferon genes (STING) activation. In vivo studies showed that excessive FA induced AKI features in mice, such as elevated serum creatinine (SCr) and blood urea nitrogen (BUN) levels, accompanied by pathological damage to kidney tissues. The above AKI characteristics induced by FA were alleviated by FU/PVP-NAR. FU/PVP-NAR also inhibited the decrease in antioxidant enzyme levels in kidney tissues induced by FA. Furthermore, in vivo mechanism studies indicated that FU/PVP-NAR inhibited the release of inflammatory factors by inhibiting DNA damage-cGAS-STING pathway. In summary, this study provided the possibility for FU/PVP-NAR as a potential candidate drug for treating FA induced AKI.
研究领域:
药理学
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肾脏病学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-21
·
IF 10.6
Li Fupeng,Mao Zhiyuan,Du Yun,Cui Yuehan,Yang Shengbing,Huang Kai,Yang Jian,Li Zhuoyuan,Liu Yihao,Gu Jinlou,Wang Danru,Wang Chen
Excessive production of reactive oxygen species (ROS) and inflammation are the key problems that impede diabetic wound healing. In particular, dressings with ROS scavenging capacity play a crucial role in the process of chronic wound healing. Herein, Zr-based large-pore mesoporous metal–organic frameworks (mesoMOFs) were successfully developed for the construction of spatially organized cascade bioreactors. Natural superoxide dismutase (SOD) and an artificial enzyme were spatially organized in these hierarchical mesoMOFs, forming a cascade antioxidant defense system, and presenting efficient intracellular and extracellular ROS scavenging performance. In vivo experiments demonstrated that the SOD@HMUiO-MnTCPP nanoparticles (S@M@H NPs) significantly accelerated diabetic wound healing. Transcriptomic and western blot results further indicated that the nanocomposite could inhibit fibroblast senescence and ferroptosis as well as the stimulator of interferon genes (STING) signaling pathway activation in macrophages mediated by mitochondrial oxidative stress through ROS elimination. Thus, the biomimetic multi-enzyme cascade catalytic system with spatial ordering demonstrated a high potential for diabetic wound healing, where senescence, ferroptosis, and STING signaling pathways may be potential targets. Graphical Abstract
Schematic diagram showing the proposed mechanism that S@M@H NPs promoted diabetic wound healing
研究领域:
生物医学工程
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分子生物学
·
药剂学
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DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2025
·
IF 7.3
Ziyan Wang,Wei Zhang,Ziyan Liu,Danyang Huang,Huiwen Kang,Jingyu Wang,Guangyu Jiang,Ai Gao
BDE-209 has a causal relationship with adverse health outcomes. However, research on its effect on bone homeostasis is relatively lacking. This study examined the relationship between BDE-209 exposure and bone health, as well as the underlying mechanisms, using both in vitro and in vivo models. In animal studies, female SD rats were administered BDE-209 for 60 days. Bone mineral density, bone microstructure, gut microbiota, and inflammaging markers were measured. Furtherly, THP-1 cell-derived macrophages were treated with a culture medium containing population-relevant dose of BDE-209 or sodium butyrate. The expression of M1 macrophage markers, osteoclast markers, and inflammatory cytokines was measured. Then macrophages were induced by osteoclast conditioned medium to evaluate the effect of BDE-209 on their differentiation into osteoclasts. Results showed reduced humeral bone density, enhanced osteoclast activity, upregulation of IL-1β, TNF-α, IL-6, and activation of PGC-1α/NAD + /cGAS-STING in the exposed group. 16s sequencing revealed that BDE-209 disrupts the abundance of the gut microbiota, notably a reduction in Lachnospiraceae . In vitro, BDE-209 can stimulate macrophages to differentiate more osteoclasts and activate the cGAS-STING pathway, while sodium butyrate can inhibit these effects. This study reveals that gut microbiota dysbiosis is involved in BDE-209-induced bone homeostasis disorder through inflammatory aging and sodium butyrate can mitigate this effect. Overall, this study provides research data for the precaution and treatment of osteoporosis associated with BDE-209 exposure.
研究领域:
毒理学
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免疫学
·
骨生物学
·
微生物学
·
药理学
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DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2023
·Vol. 20
·期 1
·1-21
·
IF 9.3
Li Nan,Wang Chunyan,Zhao Yuying,Wang Yigang,Gao Tianyu,Yu Yonghao,Wang Guolin,Zhang Linlin
Background Patients receiving epidural or intrathecal opioids administration for neuraxial analgesia frequently suffer from an irritating itch. STING (stimulator of interferon genes), an innate immune modulator, is strongly implicated in pain pathogenesis via neuron-immune modulation. Given that pain and itch share some common neurocircuits, we evaluate the therapeutic potential of STING agonists in opioid-induced itch and chronic itch.Methods Opioids (morphine, fentanyl and sufentanil) were intrathecally injected to induce acute itch. Chronic itch was induced by dry skin and contact dermatitis. Opioids analgesic effect, itch-induced scratching behavior, spinal expression of STING, phosphorylation of TBK1 (tank-binding kinase 1), IRF3 (interferon regulatory factor-3) and ERK (extracellular signal-regulated kinase), as well as production of IFN-α and IFN-β were examined. STING agonists (DMXAA and ADU-S100), TBK1 inhibitor, recombinant IFN-α and IFN-β elucidated the mechanism and treatment of itch. Whole-brain functional connectivity was evaluated using resting-state fMRI.Results We report the primary expression of STING protein by the spinal dorsal horn neurons. Intraperitoneal injection of DMXAA dose-dependently reduces morphine-induced scratch bouts, without impairing morphine antinociception. Simultaneously, DMXAA alleviates fentanyl- and sufentanil-induced itching-like behavior, and chronic scratching behavior caused by dry skin and contact dermatitis. Furthermore, DMXAA drastically increases spinal phosphorylation of TBK1 and IRF3 following morphine exposure, dry skin and contact dermatitis. DMXAA-induced anti-pruritus effects and spinal productions of IFN-α and IFN-β are compensated by intrathecal delivery of the TBK1 inhibitor. Also, ADU-S100, recombinant IFN-α and IFN-β exhibits remarkable attenuation in scratching behaviors after morphine injection and dermatitis. Recombinant IFN-α inhibits morphine-induced spinal phosphorylation of ERK. Finally, DMXAA prevents dermatitis-induced the increase of cerebral functional connectivity between regions of interests such as primary somatosensory cortex, piriform cortex, retrosplenial cortex, colliculus and ventral thalamus.Conclusion sSTING activation confers protection against opioid-induced itch and chronic itch through spinal up-regulation of TBK1-IRF3-type I interferon cascades in mice, suggesting that STING agonists are promising candidates in translational development for pruritus relief.
研究领域:
神经科学
·
免疫学
·
药理学
·
分子生物学
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DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2026
·
IF 29.1
Shi Chen,Mengjia Shi,Yi Chen,Yong Wang,Yi Li,Dayong Yang,Jinhong Guo,Cuiping Mao
Triple-negative breast cancer (TNBC) is associated with poor prognosis due to its highly heterogeneous tumor immune microenvironment and the lack of actionable molecular targets, which collectively limit the efficacy of current therapies. To address these challenges, PEI/siENPP1@Mn-ZIF-8 (PEMZ) is reported, an integrated gene–chemodynamic–immune nanocomplex that activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway through a previously unattainable triple-activation mechanism. PEMZ efficiently encapsulates siENPP1, protects it from degradation, and enables acid-responsive cytosolic release, resulting in sustained ectonucleotide pyrophosphatase/phosphodiesterase 1 ( ENPP1 ) silencing and accumulation of tumor-derived cyclic 2′,3′-GMP-AMP (cGAMP). Simultaneously, the Mn 2+ /Zn 2+ ions released from the trienzyme-mimetic nanocomplex, which exhibits peroxidase-, catalase-, and glutathione peroxidase-like activities, amplify intracellular reactive oxygen species, deplete glutathione, and trigger mitochondrial dysfunction. This coordinated redox disruption induces immunogenic cell death and further enhances STING signaling. In vitro and in vivo studies demonstrate that PEMZ markedly suppresses TNBC proliferation and metastasis, promotes dendritic cell maturation, and increases intratumoral CD8 + T-cell infiltration, achieving potent tumor inhibition with minimal systemic toxicity. This work establishes PEMZ as a mechanistically integrated nano-immunotherapy platform, offering a promising and broadly applicable strategy for the precision treatment of TNBC and other ENPP1-overexpressing cancers.
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PubMed
高影响因子
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