ACS Applied Nano Materials
·
2026
·
IF 5.8
Zhou Bi,Xia Liang,Miao Gengyun,Song Hongmei,Liu Liheng,Liu Jingjing
The
treatment effectiveness for hepatocellular carcinoma (HCC)
is often hindered by an immunosuppressive tumor microenvironment (TME),
marked by persistent hypoxia and a high presence of tumor-promoting
M2-like tumor-associated macrophages (TAMs). To overcome these barriers,
we engineered a dual-targeting biomimetic nanozyme, MnO 2 @Reg-SPARC (MRS), designed for synergistic immunochemotherapy. This
flower-like manganese dioxide nanozyme was functionalized with SPARC
antibodies to specifically target both HCC cells and M2-like TAMs,
facilitating the delivery of the multikinase inhibitor Regorafenib
(Reg). Bioinformatic and experimental validations showed that SPARC-antibody
functionalization enhanced nanoparticle accumulation in HCC cells
and IL-4-induced M2-like macrophages. The MRS nanosystem exhibited
excellent stability and pH/H 2 O 2 -responsive drug
release. MnO 2 functioned as a catalase-mimetic nanozyme,
breaking down H 2 O 2 to generate O 2 , which reduced tumor hypoxia and boosted the immunomodulatory effects
of Reg. Reg demonstrated both antitumor and angiogenesis inhibition
properties in tumor cells. MRS treatment effectively reprogrammed
the immune response by activating the STING/IRF3 signaling pathway,
facilitating the shift of macrophages from a pro-tumor M2-like phenotype
to an antitumor M1-like phenotype. In vivo studies further revealed
that MRS achieved prolonged blood circulation and superior tumor accumulation,
resulting in robust tumor growth inhibition with negligible systemic
toxicity. This biomimetic platform provides a dual-targeting approach
that combines hypoxia relief, targeted chemotherapy, and innate immune
reprogramming to precisely treat hepatocellular carcinoma.
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高影响因子
Journal of Translational Medicine
·
2025
·Vol. 23
·期 1
·1-15
·
IF 7.5
Li Yuan,Liu Wenna,Fan Xushen,Wu Xinyi,Cao Mingbo,Li Xiuling,Wurita Amin,Sun Suofeng
Background Hepatocellular carcinoma (HCC), characterized by its aggressive trait and rapid progression, stands as one of the leading causes of cancer-related death worldwide. Fas apoptotic inhibitory molecule (FAIM), a death receptor antagonist, impedes cell apoptosis by reinforcing protein phosphorylation and stability. High mobility group A1 (HMGA1) is reported to be subject to multiple posttranslational modification, and plays a crucial role in HCC development. However, whether FAIM facilitates tumorigenesis through modulating HMGA1 phosphorylation remains unclear.Methods We applied Huh7 and SNU387 cells to investigate the regulatory role of FAIM in cell proliferation and apoptosis. Next, we constructed a male BALB/C mouse model with HCC to explore the biological function of FAIM in tumor growth. Subsequently, anti-FAIM proteomic and phosphorylation proteomic profiles were performed to screen HMGA1 as the FAIM-modulated downstream phosphorylated protein. Eventually, a series of immunoprecipitation (IP) tests and in vitro kinase assay revealed the crosstalk of FAIM, cyclin-dependent kinase7 (CDK7) and HMGA1, and unveiled the vital value of FAIM in HCC pathogenesis.Results In vitro and in vivo experiments validated that FAIM overexpression was advantageous for HCC progression. Thereafter, anti-FAIM proteomic profile identified that FAIM interacted with CDK7 and HMGA1. Phosphorylation proteomic profile revealed that the Ser36 of HMGA1 was a downstream phosphorylation site of FAIM. Consistently, Co-IP and cycloheximide assays verified that FAIM enhanced HMGA1 phosphorylation and stability. More importantly, recovery experiments identified that silencing HMGA1 altered the regulatory role of overexpressed FAIM in Huh7 cells. Furthermore, we transduced Flag-HMGA1WT or Flag-HMGA1S36A plasmids into overexpressed FAIM cells and demonstrated that Ser36 phosphorylation influenced HMGA1 stability.Conclusion sSummarily, we elucidated that FAIM modulated HCC progression through facilitating the interaction of CDK7 and HMGA1 as well as elevating HMGA1 phosphorylation and stability.Graphical abstract
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PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Mengyun Peng,Hongyan Dong,Meiyu Shao,Xiaoqing Zhang,Jiamei Sun,Chuan Ding,Xin Han,Qiao Yang,Xianan Sang,Gang Cao
Hepatocellular carcinoma (HCC) is an immunosuppressive tumor associated with high mortality. Photothermal and photodynamic therapies have been applied to induce immunogenic cell death (ICD) in HCC, successfully eliciting immune responses but facing limitations in penetration depth in clinical trials . Here, intrinsic mitochondrial hyperthermia was used to trigger thermosensitive drug release. The mitochondria were further self-heated through 2,4-dinitrophenol uncoupling, dramatically promoting free radical initiation and inducing tumor ICD. The synthesized mitochondrial-targeting TPP-HA-TDV nanoparticles specifically generated free radicals in the mitochondria without external stimulation, and obviously enhanced the release of ICD markers, subsequently evoking immune responses. The results showed that mitochondrial hyperthermia could be an endogenous target for thermosensitive drug release. Furthermore, self-heating mitochondria-induced free radical blast could be an efficient therapeutic for deep-seated tumor therapy.
研究领域:
肿瘤学
·
免疫治疗
·
纳米技术
·
细胞生物学
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高影响因子
CARCINOGENESIS
·
2021
·Vol. 42
·期 5
·753-761
·
IF 4.944
Chu Hongwei,Wu Changqing,Zhao Qun,Sun Rui,Yang Kuo,Zhao Baofeng,Liu Yang,Liang Zhen,Zhong Shijun,Zhang Lihua,Zhang Yukui
Sorafenib is commonly used to treat advanced human hepatocellular carcinoma (HCC). However, clinical efficacy has been limited by drug resistance. In this study, we used label-free quantitative proteomic analysis to systematically investigate the underlying mechanisms of sorafenib resistance in HCC cells. A total of 1709 proteins were confidently quantified. Among them, 89 were differentially expressed and highly enriched in the processes of cell–cell adhesion, negative regulation of apoptosis, response to drug and metabolic processes involving in sorafenib resistance. Notably, folate receptor α (FOLR1) was found to be significantly upregulated in resistant HCC cells. In addition, in vitro studies showed that overexpression of FOLR1 decreased the sensitivity of HCC cells to sorafenib, whereas siRNA-directed knockdown of FOLR1 increased the sensitivity of HCC cells to sorafenib. Immunoprecipitation-mass spectrometry analysis suggested a strong link between FOLR1 and autophagy-related proteins. Further biological experiments found that FOLR1-related sorafenib resistance was accompanied by the activation of autophagy, whereas inhibition of autophagy significantly reduced FOLR1-induced cell resistance. These results suggest the driving role of FOLR1 in HCC resistance to sorafenib, which may be exerted through FOLR1-induced autophagy. Therefore, this study may provide new insights into understanding the mechanism of sorafenib resistance.
研究领域:
肿瘤学
·
分子生物学
·
药理学
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PubMed
高影响因子
MOLECULAR THERAPY
·
2026
·
IF 11.4
Ye Chen,Jiaxin Bei,Xinkun Huang,Yujun Cai,Han Xu,Kangshun Zhu,Yihu Li,Chengyu Jia,Jiabai Huang,Zebing Song,Yongjian Guo,Zhe-Sheng Chen,Weiguo Cai,Bixiang Zhan,Mingyue Cai,Yin Zhang,Wensou Huang
Insufficient microwave ablation (iMWA) of hepatocellular carcinoma (HCC) often leads to rapid and aggressive recurrence, and effective intervention remains a formidable challenge. Here, we show that the DNA methylation machinery is aberrantly activated in residual HCC following iMWA. The heat-responsive stress protein HSP90α collaborates with the deubiquitinase USP7 to stabilize and upregulate DNA methyltransferase DNMT1, thereby transducing the sublethal heat-stress input from iMWA into an epigenetic output and elevating DNA methylation levels. Sublethal heat-stress-induced DNMT1 upregulation significantly promotes the growth and invasive potential of post-iMWA residual HCC cells, a process that involves disruption of propionate metabolism. Mechanistically, the propionate-metabolizing enzyme ACSS3 in residual HCC is found to be silenced by DNMT1-mediated promoter hypermethylation, impairing propionate-to-propionyl-coenzyme A (CoA) conversion. Reduction in propionyl-CoA production enhances the activity of the fatty acid β-oxidation (FAO) rate-limiting enzyme carnitine palmitoyltransferase 1 (CPT1), ultimately stimulating FAO-dependent ATP regeneration. Critically, we developed a liposomal CRISPR-dCas9-based locus-specific demethylation system for precise epigenetic reactivation of ACSS3 and demonstrated its ability to effectively prevent post-iMWA HCC recurrence and metastasis, with more pronounced efficacy when combined with propionate supplementation. Our findings identify a novel DNMT1-driven “epigenetic-metabolic cascade” as a central mechanism promoting HCC recurrence following iMWA, emphasizing the therapeutic potential of ACSS3 -targeted methylation editing.
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高影响因子
ACTA PHARMACOLOGICA SINICA
·
2025
·
IF 8.4
Mu Wei,Shi Ya-ge,Jian Yu-lun,Li Lei,Zhou Yan-feng,Wang Hui,Ge Yang
The progression of hepatocellular carcinoma (HCC) is partly driven by reactive oxygen species (ROS)-induced tissue damage and inflammation. Nicotinamide adenine dinucleotide phosphate oxidases (NOXs) are key regulators of ROS production, yet the specific role of NOX1 in HCC progression and therapeutic response remain incompletely understood. In this study we investigated the critical role of NOX1 in progression, metastasis and therapeutic sensitivity of HCC, and explored its potential as a therapeutic target. By comprehensive analysis of public databases and validation with in-house clinical specimens, we showed that NOX1 expression was significantly elevated in metastatic HCC that was correlated to poor patient prognosis. Knockdown of NOX1 or pharmacological inhibition with a selective NOX1 inhibitor ML171 significantly reduced ROS production and suppressed HCC cell motility and invasion in vitro. NOX1 inhibition also attenuated HCC metastasis in experimental metastasis mouse model using direct injection of HCC cells, and mitigated CCl 4 -induced liver injury and pro-tumorigenic microenvironment in CCl 4 -induced chronic liver injury and spontaneous tumor development mouse model. Importantly, we demonstrated that combined sorafenib or radiotherapy with NOX1 inhibition synergistically reduced the metastatic potential of HCC cells and enhanced the therapeutic efficacy. Bioinformatics analysis revealed that NOX1 contributed to HCC metastasis and therapy resistance by modulating ROS homeostasis, cellular antioxidant systems and inflammatory pathways. Taken together, this study elucidates the critical role of NOX1 in HCC pathogenesis, suggesting that NOX1 inhibition represents a promising strategy to overcome resistance and enhance HCC sensitivity to sorafenib and radiotherapy.
研究领域:
肿瘤学
·
分子生物学
·
药理学
·
放射治疗学
·
细胞生物学
·
癌症研究
·
肝病学
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高影响因子
EUROPEAN POLYMER JOURNAL
·
2026
·
IF 6.8
Guolong Zhang,Wenjing Feng,Chenying Liu,Linhua Wang,Cui Cheng,Xiao Han,Wenjuan Chen
This study develops a multifunctional hydrogel that achieves highly effective treatment of hepatocellular carcinoma (HCC) by combining phototherapy with immunotherapy and remodeling tumor microenvironment (TME). The hydrogel is prepared via dynamic Schiff base crosslinking between carboxymethyl chitosan and four-arm PEG benzaldehyde, incorporating polyvinylpyrrolidone-modified Bi 2 WO 6-x (BWO-PVP) nanoparticles and fucoidan (Fu). In vitro studies demonstrate that the hydrogel exhibites good self-healing properties, injectability, and TME-responsive degradation behavior. Under 808 nm laser irradiation, it generates substantial hyperthermia and reactive oxygen species, leading to significant inhibition of HepG2 cell proliferation. Moreover, the hydrogel can release Fu to suppresse the activation of cancer-associated fibroblasts (CAFs), which contributing to TME remodeling. In H22 hepatoma-bearing mice, the hydrogel can also load the STING agonist (cyclic dinucleotide, CDN), thereby suppressing tumor growth and reversing immunosuppressive TME conditions. Hence, this combinatory strategy provides a promising platform for enhancing HCC treatment through integrated phototherapy, TME regulation and immunotherapy.
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Xiaoxuan Li,Hongyun Zhang,Yufei Deng,Fang qian,Xiaohui Zhang,Shuiping Ding,Xiaoying Hou,Hongzhi Du
Liver cancer was the third cause of global cancer death, while China has the largest number of patients. And traditional Chinese medicine is an important strategy for liver cancer. There into, Huaier polysaccharides (HP), the major component of Trametes robiniophila Murr., as a preparation of Huaier granule, is recommended by clinical guidelines for Hepatocellular carcinoma (HCC). However, the anti-HCC mechanism remains unclear. Herein, we investigated whether HP could suppress HCC and revealed the underlying mechanism. Firstly, HP showed a weaker proliferation inhibitory effect on the mouse source and human HCC cells in vitro , but exhibited stronger anti-HCC effects in animals. And nude mice models confirmed that macrophages play an important role in the anti-HCC effect of HP. Then, we observed that HP reduced the polarization of M2 macrophages in tumor microenvironment and increased the secretion of pro-inflammatory factors by macrophages. Moreover, 16 s rRNA gene sequencing and non-targeted metabolomics analysis revealed that HP altered the gut microbiota and related metabolites. Eventually, antibiotic intervention eliminated the efficacy and reduced the expression of pro-inflammatory factors, confirming that the gut microbiota is a key molecule for HP efficacy. In addition, MTT and EdU assay indicated that Chenodeoxycholic acid (CDCA) were potential microbial metabolites influencing efficacy of HP. In conclusion, our data revealed that Huaier polysaccharides inhibited HCC via gut microbiota mediated M2 macrophage polarization, providing sufficient scientific support for Huaier polysaccharides clinical application and indicating the indispensable role of polysaccharides in life health.
研究领域:
肿瘤学
·
微生物学
·
免疫学
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中医药学
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药理学
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高影响因子
ONCOGENE
·
2020
·Vol. 39
·期 11
·2408-2423
·
IF 7.971
Guan Yun-feng,Huang Qiao-ling,Ai Yuan-li,Chen Qi-tao,Zhao Wen-xiu,Wang Xiao-min,Wu Qiao,Chen Hang-zi
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
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高影响因子
MICROCHIMICA ACTA
·
2025
·Vol. 192
·期 9
·1-15
·
IF 5.3
Xue Boyang,Li Qiang,Xing Yanjiao,Mu Hongkai,Yang Yongzhen,Chen Lin,Yu Shiping,Guo Rongrong
To overcome the dual challenges of suboptimal therapeutic outcomes and delayed detection in hepatocellular carcinoma (HCC), a nucleus-targeting theranostic nanoplatform based on gadolinium-functionalized carbon dots (GdCDs) is presented. GdCDs were synthesized via a one-step hydrothermal method utilizing neutral red and citric acid as carbon precursors and gadolinium chloride hexahydrate as the paramagnetic source, showing good fluorescence (FL) and magnetic resonance imaging (MRI) capabilities. After modified with a nuclear localization sequence (NLS), GdCDs were loaded with doxorubicin (DOX) to yield the integrated theranostic platform: Nucleus-targeting gadolinium-functionalized carbon dot drug delivery system (NT-GdCDs-DDS) for FL/MRI dual-modality imaging and nucleus-targeting drug delivery. NT-GdCDs-DDS exhibited optimal excitation/emission wavelengths at 497/596 nm, a high longitudinal relaxivity (r 1 ) of 23.11 mM −1 s −1 , and a DOX loading efficiency of 61.9%. Results of antitumor activity assays in vitro demonstrated the viability of HepG2 cells incubated with 400 μg/mL NT-GdCDs-DDS for 24 h was 8.12%, demonstrating strong antitumor activity. Furthermore, a significant tumor growth suppression in mice was observed by treated with NT-GdCDs-DDS over a 15-day period, showing superiority to free DOX. These findings establish NT-GdCDs-DDS as a potent theranostic nanoplatform for simultaneous HCC imaging and therapy. Graphical abstract
研究领域:
纳米医学
·
肿瘤学
·
诊断成像
·
药物递送系统
·
生物工程
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-18
·
IF 10.6
Yang Huizhen,Mu Weiwei,Yuan Shijun,Yang Han,Chang Lili,Sang Xiao,Gao Tong,Liang Shuang,Liu Xiaoqing,Fu Shunli,Zhang Zipeng,Liu Yongjun,Zhang Na
Immune checkpoint inhibitors (ICIs) combined with antiangiogenic therapy have shown encouraging clinical benefits for the treatment of unresectable or metastatic hepatocellular carcinoma (HCC). Nevertheless, therapeutic efficacy and wide clinical applicability remain a challenge due to “cold” tumors’ immunological characteristics. Tumor immunosuppressive microenvironment (TIME) continuously natural force for immune escape by extracellular matrix (ECM) infiltration, tumor angiogenesis, and tumor cell proliferation. Herein, we proposed a novel concept by multi-overcoming immune escape to maximize the ICIs combined with antiangiogenic therapy efficacy against HCC. A self-delivery photothermal-boosted-NanoBike (BPSP) composed of black phosphorus (BP) tandem-augmented anti-PD-L1 mAb plus sorafenib (SF) is meticulously constructed as a triple combination therapy strategy. The simplicity of BPSP's composition, with no additional ingredients added, makes it easy to prepare and presents promising marketing opportunities. (1) NIR-II-activated BPSP performs photothermal therapy (PTT) and remodels ECM by depleting collagen I, promoting deep penetration of therapeutics and immune cells. (2) PTT promotes SF release and SF exerts anti-vascular effects and down-regulates PD-L1 via RAS/RAF/ERK pathway inhibition, enhancing the efficacy of anti-PD-L1 mAb in overcoming immune evasion. (3) Anti-PD-L1 mAb block PD1/PD-L1 recognition and PTT-induced ICD initiates effector T cells and increases response rates of PD-L1 mAb. Highly-encapsulated BPSP converted 'cold' tumors into 'hot' ones, improved CTL/Treg ratio, and cured orthotopic HCC tumors in mice. Thus, multi-overcoming immune escape offers new possibilities for advancing immunotherapies, and photothermal/chemical/immune synergistic therapy shows promise in the clinical development of HCC.Graphical Abstract
研究领域:
癌症生物学
·
药学
·
生物医学工程
·
免疫治疗
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高影响因子
Cell Reports Medicine
·
2025
·
IF 10.6
Shuai Yang,Xinyao Qiu,Yingcheng Yang,Jing Wu,Shan Wang,Bo Zheng,Jianmin Wu,Tao Zhou,Yangqianwen Zhang,Mixue Bai,Shuowu Liu,Zihan Zhao,Yani Zhang,Yixian Wang,Jinxia Bao,Mengye Wu,Dongdong Xue,Meiyu Bao,Ji Hu,Siyun Shen,Hongyang Wang,Lei Chen
Leukotriene A4 hydrolase (LTA4H), an inflammatory mediator, has garnered attention for its role in the development of chronic lung diseases and various cancers. Our study highlights the protective role of LTA4H in hepatocellular carcinoma (HCC) occurrence and progression. LTA4H is downregulated in clinical and mouse HCC tumors. LTA4H deficiency exacerbates hepatocyte damage by restraining JNK activation and promotes CD206 + macrophage polarization through the upregulation of LTBP1 expression and downstream transforming growth factor β (TGF-β) secretion and activation. Mechanistically, LTA4H induces heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) phosphorylation, enhancing their interaction and leading to the functional inhibition of HNRNPA1 in regulating Ltbp1 mRNA maturation and processing in the nucleus. LTA4H-deficient patients exhibit poor prognosis and immunotherapy resistance. Combination therapy targeting TGF-β and PD-1 significantly improves the immunotherapy resistance of LTA4H-knockout Hepa1-6 tumors. Our findings reveal the previously unreported role of LTA4H in regulating the tumor microenvironment and provide insights into potential diagnostic and therapeutic strategies for patients with LTA4H-deficient HCC.
研究领域:
肿瘤学
·
分子生物学
·
免疫学
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PubMed
高影响因子
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