ACS Nano
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2025
·
IF 16
Yuai Li,Yunting Zhang,Jingwen Wang,Yujie Che,Tao Gong,Zhirong Zhang,Renhe Liu,Yao Fu
Selective autophagy relies on multivalent recognition by receptors like SQSTM1/p62 to form aggregates that cluster disperse organelles, undergoing liquid–liquid phase separation to facilitate their clearance and maintain cellular homeostasis. Inspired by this, we present the multivalent nanoparticle-based organelle targeting chimera (NanoTACOrg) to efficiently degrade organelles by flexibly clustering organelles for sequestration and facilitating targeted recruitment of autophagosomes. NanoTACOrg, assembled with a PLGA core, lysosomal escape modules, organelle-targeting modules, and LC3B binding modules, is programmed to selectively degrade various organelles, including mitochondria, endoplasmic reticulum, and Golgi apparatus. After endocytosis and lysosomal escape, NanoTACOrg targets subcellular compartments and mimics p62 aggregate-driven organelle clustering and degradation, without exhibiting the “hook effect”. Specifically, NanoTACMito-mediated mitochondrial degradation disrupts oxidative phosphorylation (OXPHOS) while enhancing compensatory glycolysis, thus sensitizing tumor cells to the glucose transporter 1 (GLUT1) inhibitor BAY-876. BAY-876 loaded NanoTACMito potently inhibits tumor growth, recurrence, and metastasis, demonstrating superior therapeutic efficacy by simultaneously targeting OXPHOS and glycolysis. These findings highlight the potential of NanoTACOrg as a versatile and effective platform for cancer therapy, particularly through organelle-specific degradation and metabolic reprogramming.
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高影响因子
Journal of Cancer
·
2022
·
IF 4.478
Kezhong Tang,Qing Chen,Yanmo Liu,Lantian Wang,Wenjie Lu
Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Sorafenib is the first small-molecule multi-kinase inhibitors approved by FDA for treatment of advanced HCC. Metformin has been demonstrated to have benefit for preventing cancer progression. In human recurrent HCCs, NF-E2-related factor 2 (Nrf2) was overexpressed and associated with poor survival. Nrf2 related signaling pathway plays central role to mediate cellular resistance to sorafenib through protecting HCC cells from ferroptosis. The effect of Combination treatment for HCC cells and the intrinsic mechanism have not been reported. In this study, metformin augmented the anti-tumor effect of sorafenib for HCC through ferroptosis induction by inhibiting Nrf2 related pathway. Based on the results of Nrf2 knockdown and p62 knockdown study, the combination of sorafenib and metformin suppressed proliferation of HCC cells through p62-Keap1-Nrf2/HO1 signaling way. Size of xenografts treated with the combination of sorafenib and metformin was smaller than other groups in vivo . Moreover, the combination treatment greatly induced ferroptosis in HCC cells through inhibiting Nrf2 expression. Based on our findings, the combination treatment suppressed proliferation of HCC cells through ferroptosis induction, by p62-Keap1-Nrf2/HO1 signaling way.
研究领域:
肿瘤学
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分子生物学
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药理学
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PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2025
·
IF 2.8
Mengmeng Gao,Hao Ling,Chengxiang Guo,Yinan Hu,Jing Zhu,Jicang Wang
Cadmium, a bluish-white metallic, possesses a prolonged half-life in organisms, causing damage to multiple tissues and organs. Naringenin, a natural flavonoid antioxidant, mitigates cadmium-induced damage in organisms. However, the mechanism by which naringenin attenuates Cd-associated hepatocellular damage has not been fully elucidated. The present investigation consequently aimed to elucidate the mechanistic involvement of autophagy in cadmium hepatotoxicity using the rat model, with parallel assessment of naringenin's hepatoprotective efficacy. In this experiment, 24 SD rats underwent randomization to four experimental groups: (1) control (intraperitoneal saline injection), (2) Cd (1 mg/kg b.w. CdCl₂ intraperitoneal injection), (3) Cd + Nar (1 mg/kg b.w. CdCl₂ injection + 50 mg/kg b.w. naringenin oral gavage), and (4) Nar (50 mg/kg b.w. naringenin oral gavage) groups. After the 14-day interventions, serum and liver tissues were collected post-euthanasia. Hepatic injury markers (AST and ALT) and antioxidant enzymes (CAT and SOD) were quantified. Histopathology utilized HE and TUNEL staining. RT-qPCR and western blot analyses determined mRNA and protein expression levels of autophagy-related factors (p62 and LC3) and apoptosis-related factor (Caspase-3). The results demonstrated that cadmium exposure significantly reduced body weight, increased relative liver weight, elevated serum AST/ALT levels, and diminished hepatic CAT/SOD activity. Cadmium significantly upregulated both mRNA and protein expression levels of p62 and Caspase-3 while suppressing LC3 expression. Naringenin co-administration attenuated cadmium-induced hepatic injury, oxidative stress, impaired autophagy, and enhanced apoptosis. These findings collectively demonstrate that cadmium exposure induces hepatic injury and oxidative stress in rats through autophagy inhibition and apoptotic activation, while naringenin exerts protective effects by modulating these pathological processes.
研究领域:
毒理学
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药理学
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细胞生物学
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生物化学
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分子生物学
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PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Chenghao Bi,Yawei Zhao,Jinxia Wei,Wenjie Bi,Songsong Wang,Luyao Hu,Yujia Gu,Liu Yang,Huiru Liu,Liwen Han,Yubo Li
SSA alleviates poly(I:C)-induced viral-like acute lung injury. • SSA restores mitochondrial homeostasis by recovering mitophagy flux. • eIF3f is identified as a direct molecular target of SSA. • SSA inhibits p62 K48-linked ubiquitination via eIF3f to relieve mitophagy blockade. Background Acute lung injury (ALI) is marked by an exaggerated inflammatory response, elevated oxidative stress, and impaired mitochondrial function, while effective targeted therapeutic strategies remain scarce. Saikosaponin A (SSA), a major active component of Bupleurum , exhibits anti-inflammatory activity, yet its direct targets and mechanisms in viral ALI remain unclear. Purpose This study aims to determine the mechanism of action and molecular target of SSA in viral ALI. Methods Poly(I:C)-induced viral-mimetic ALI models were established in both mice and BEAS-2B cells to explore the protective effects of SSA. Mitochondrial function was evaluated by detecting mitochondrial membrane potential, mitochondrial reactive oxygen species (MitoROS) levels, mitochondrial permeability transition pore (mPTP) opening, and oxygen consumption rate (OCR). Autophagy and mitophagy flux were further assessed via Western blotting, immunofluorescence staining, transmission electron microscopy (TEM), and the mCherry-GFP-LC3B reporter assay. Potential molecular targets of SSA were identified through drug affinity responsive target stability combined mass spectrometry (DARTS-MS), cellular thermal shift assay (CETSA), molecular docking, molecular dynamics simulation, and surface plasmon resonance (SPR), followed by validation using small interfering RNA (siRNA), single guide RNA (sgRNA), and adeno-associated virus (AAV)-mediated eif3f knockdown. Results SSA significantly mitigated poly(I:C)-triggered pulmonary inflammatory responses, oxidative stress, and lung tissue injury. Mechanistically, poly(I:C) induction caused mitochondrial dysfunction and mitophagy flux blockade, accompanied by the accumulation of LC3B and p62. SSA restored mitochondrial homeostasis by restoring mitophagy flux, rather than merely activating general autophagy. Further experiments identified eIF3f as a direct binding target of SSA. SSA suppressed abnormal K48-linked ubiquitination of p62 through targeting eIF3f, thereby maintaining p62 stability and alleviating mitophagy flux blockade. Deficiency of eIF3f markedly attenuated the protective effects of SSA. Conclusion SSA alleviates viral-like ALI by targeting eIF3f to regulate p62 ubiquitination and restore mitophagy flux, thereby identifying a novel SSA-eIF3f-p62 regulatory axis. During viral acute lung injury, excessive ROS production and inflammation severely impair mitochondrial function, leading to aberrant activation of mitophagy accompanied by marked blockage of autophagic flux. SSA targets eIF3f and regulates the ubiquitination-driven accumulation of p62, thereby modulating the p62-mediated selective autophagy pathway. This regulation restores mitophagic flux, improves mitochondrial function, and ultimately alleviates acute lung injury. Download: Download high-res image (179KB) Download: Download full-size image
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高影响因子
ENVIRONMENTAL RESEARCH
·
2026
·
IF 8.2
Minming Chen,Yongjie Liu,Wenwen Qu,Qianlong Zhang,Fei Li,Yi Wang,Xuan Zhai
Per- and polyfluoroalkyl substances (PFASs) are persistent environmental contaminants closely linked to metabolic liver disease; however, the transgenerational hepatotoxicity and underlying mechanisms of emerging PFAS substitutes remain poorly understood. Herein, we focused on 6:2 polyfluoroalkyl phosphate diester (6:2 diPAP), a prominent PFAS substitute, to evaluate its developmental hepatotoxicity. By integrating zebrafish phenotyping, transcriptomic feature selection, virtual gene knockout, and experimental validation, we characterized the candidate molecular events through which 6:2 diPAP triggers non-alcoholic fatty liver disease (NAFLD)-like injury in offspring. Early-life exposure to environmentally relevant concentrations of 6:2 diPAP from 0 to 5 dpf, particularly 500 ng/L, induced persistent hepatic lipid accumulation, hepatic vacuolation, and metabolic disturbances in zebrafish at 28 dpf. Integrated network and transcriptomic analyses identified sequestosome 1 (SQSTM1) as a key stress-responsive hub associated with pathological hepatocyte remodeling. Quantitative real-time polymerase chain reaction (RT-qPCR) and immunofluorescence analyses further demonstrated exposure-responsive increases in sqstm1 expression and SQSTM1/p62 protein fluorescence intensity, with the strongest changes observed in the 500 ng/L group. Human single-nucleus RNA-seq and pseudotime analyses revealed that SQSTM1-high hepatocytes were enriched in injury-associated and senescence-associated states during NAFLD progression, suggesting a link between SQSTM1 activation and hepatocyte-state deterioration. Furthermore, virtual SQSTM1 knockout in NASH hepatocytes predicted oxidative stress, xenobiotic metabolic, and inflammatory rewiring. Molecular docking predicted a feasible 6:2 diPAP-SQSTM1 interaction with a binding affinity of −6.0 kcal/mol, and 200 ns molecular dynamics simulation supported the structural plausibility of the ligand-protein complex. Collectively, this study proposes a 6:2 diPAP-SQSTM1-hepatocyte remodeling axis and provides a comprehensive framework linking early-life PFAS exposure with hepatocyte-state transition and NAFLD-like metabolic dysfunction.
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高影响因子
Cell Reports
·
2025
·Vol. 44
·期 12
·
IF 6.9
Yunfei Zhou,Xinxin Yang,Jianwen Xu,Yidi Wu,Yin Fu,Yihong Dong,Xun Yang,Qiang Fu,Chenxu Guo,Yunjing Hou,Shuyuan Chang,Jun Yan,Ju Ran,Yumeng Wang,Qingxin Zhang,Tomii Ayaka,Lei Yu,Feng Geng,Liuyang Zhao,Xiaoyang Hu,Shuijie Li,Hongxue Meng,Dabin Liu
Dysregulated cholesterol synthesis fuels cancer progression, but its precise role in hepatocellular carcinoma (HCC) remains unclear. Here, we identify elevated acetylation of 24-dehydrocholesterol reductase (DHCR24) at Lys254 as a hallmark of HCC. Both total DHCR24 and its K254 acetylation independently predict poor patient survival. Acetylation stabilizes DHCR24, sustaining hepatic cholesterol synthesis and promoting tumorigenesis. Mechanistically, DHCR24 acetylation enhances 7-ketocholesterol accumulation, which upregulates p62 and drives HCC growth in vitro and in vivo . Pharmacologic inhibition of DHCR24 expression and acetylation with the US Food and Drug Administration (FDA)-approved drug irbesartan suppresses cell proliferation and reduces tumor burden in xenograft and carcinogen-induced mouse models. Reduced p62 expression parallels the antitumor effects. These findings define DHCR24 acetylation as a metabolic switch linking sterol synthesis to oncogenesis and highlight the DHCR24-7-ketocholesterol-p62 axis as a therapeutic target for HCC.
研究领域:
癌症生物学
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分子肿瘤学
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代谢调控
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肝脏病学
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转化医学
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PubMed
高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·1-16
·
IF 3.9
Feng Wenguang,Wang Haibin,Zhang Guoliang,Gao Wang,LI Hongcang,Liu Haibo,Sun Yanhong
Objective To explore the role and mechanism of transcription factor KLF4 in regulating mitochondrial damage and apoptosis by activating chondrocyte autophagy. Human primary chondrocytes were treated with IL-1β to establish an in vitro osteoarthritis model. KLF4 was overexpressed using lentivirus to intervene in chondrocytes. Cell apoptosis and mitochondrial membrane potential were detected by flow cytometry. Mitochondrial morphology was observed under transmission electron microscopy. Cell ATP level was detected by ELISA. Ca2 + homeostasis was detected by flow cytometry with Fluo-3/AM fluorescence labeling. The expression of autophagy-related proteins Beclin1, P62, and LC3 was detected by WB. The interaction between transcription factor KLF4 and gene p62 promoter was verified by dual luciferase assay. The interaction between p62, Beclin1 and KLF4 was verified by Chip assay. To further explore the relationship between KLF4 and autophagy, KLF4 was overexpressed and treated with autophagy inhibitor 3-MA (5mmol/L). The expression of autophagy-related proteins Beclin1, P62, and LC3 was detected by WB. Cell apoptosis level was detected by flow cytometry. The mitochondrial membrane potential level was detected by flow cytometry. Ca2 + homeostasis was detected by flow cytometry with Fluo-3/AM fluorescence labeling. In chondrocytes treated with IL-1β, TNF-α levels increased significantly, apoptosis rate rose, and ATP generation declined. However, after overexpression of KLF4, apoptosis level decreased significantly; ATP level increased significantly, and mitochondrial structure and function gradually recovered. Flow cytometry detection of mitochondrial membrane potential showed a significant decrease after KLF4 overexpression, and Ca2 + homeostasis was partially restored. WB detection of autophagy-related proteins showed a significant increase in p62 and cellular autophagy levels. Dual luciferase results indicated that transcription factor KLF4 interacted with the promoter of gene p62; Chip experiment results suggested that KLF4 may interact with the promoter regions of P62 and Beclin1. After KLF4 overexpression combined with 3-MA treatment, compared with empty load combined with 3-MA, p62 and LC3 protein expression increased significantly, apoptosis level decreased significantly, and membrane potential level decreased. Transcription factor KLF4 can regulate mitochondrial damage and apoptosis by activating chondrocyte autophagy.
研究领域:
分子生物学
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风湿病学
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细胞生物学
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转化医学
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骨骼疾病
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信号转导
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基因调控
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线粒体功能
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PubMed
高影响因子
Genes & Genomics
·
2022
·Vol. 44
·期 11
·1375-1384
·
IF 2.164
Wang Yazhuo,Ren Yanan,Li Na,Zhao Jing,Zhao Sufen
Background Rab11a is a novel identified tumorigenic factor involved in different cancers. Objective This study aimed to assess the biological function of Rab11a in ovarian cancer (OC). Methods GEPIA database and real-time PCR were used to determine Rab11a expression in OC tissues and normal ovarian tissues. CCK-8, cell cycle, wound healing, transwell, and enzyme linked immunosorbent assay were used to detect the effects of Rab11a knockdown or overexpression on the proliferation, migration, and invasion of OC cells. Western blot analysis of autophagy-related markers and immunofluorescence staining of LC3 were performed to determine autophagy induction in Rab11a-silenced or overexpressed OC cells. Moreover, autophagy inhibitor 3-MA was employed to clarify the effects of Rab11a-regulated autophagy on the malignant phenotypes of OC cells. Results The mRNA level of Rab11a was increased in tumor tissues from OC patients as compared to the normal ovarian tissues. Knockdown of Rab11a in OVCAR-3 cells inhibited the growth of OC cells and led to cell cycle arrest, accompanied by reduced expression of PCNA and Cyclin D1. Rab11a deficiency suppressed migration and invasion of OC cells, accompanied by decreased secretion of MMP-2 and MMP-9. Silence of Rab11a impeded autophagy induction, as evidenced by decreased LC3 puncta formation, reduced abundance of LC3II and Beclin1, and increased p62 protein expression. In contrast, the ectopic expression of Rab11a in A2780 cells exerted opposite effects. Interestingly, autophagy inhibitor 3-MA abolished the effects of Rab11a overexpression on autophagy, proliferation, migration, and invasion. Conclusions Rab11a promotes the malignant phenotypes of OC cells by inducing autophagy.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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高影响因子
FASEB JOURNAL
·
2025
·Vol. 39
·期 10
·e70670
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IF 4.2
Shushu Jiang,Shichen Bu,Xiang Kang,Yin Dong,Long Chen,Lin Yuan,Menghao Shi,Meng Du,Minglu Liang,Kai Huang,Liu Yang
Pathological cardiac hypertrophy leads to heart failure. In this study, we aimed to explore the role of transmembrane protein Tspan9 in the development of cardiac hypertrophy and failure. We found that Tspan9 was upregulated in the hearts of patients with hypertrophic cardiomyopathy (HCM), in the hearts of mice subjected to transverse aortic constriction (TAC), as well as in phenylephrine-induced hypertrophic neonatal rat cardiomyocytes (NRCMs). AAV9-mediated overexpression (OE) of Tspan9 in mouse hearts augmented TAC-induced cardiac hypertrophy and failure, while Tspan9 knockdown (KD) alleviated this effect. Tspan9-OE promotes PE-induced cardiomyocyte enlargement, whereas Tspan9-KD suppresses it. Mechanistically, we demonstrated that Tspan9 interacts with p62, a pivotal regulator of autophagy, impairs its cargo function, leading to autophagy suppression. Remarkably, the anti-hypertrophic effect of Tspan9-KD was impaired when autophagy was inactivated or p62 was knocked down. These findings suggest that Tspan9 exacerbates pressure overload-induced pathological cardiac hypertrophy and failure by suppressing cardiac autophagy through its interaction with p62. Graphical Upon pathological stimuli, Tspan9 is upregulated in the cardiomyocytes and interacts with p62. It impairs the binding of p62 to the ubiquitin chains of misfolded proteins and LC3 on phagophores. This leads to the inhibition of autophagy flux and accumulation of misfolded proteins, which ultimately results in cardiac hypertrophy and failure.
研究领域:
心脏病学
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分子生物学
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细胞生物学
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遗传学
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病理学
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高影响因子
JOURNAL OF INORGANIC BIOCHEMISTRY
·
2022
·
IF 4.336
Xueru Wang,Ruiming Hu,Chang Wang,Zejing Wei,Shaoxing Pi,Yong Li,Guyue Li,Fan Yang,Caiying Zhang
Excessive molybdenum (Mo) and cadmium (Cd) have toxic effects on animals. However, hepatotoxicity co-induced by Mo and Cd in ducks is still unclear. To evaluate the effects of Cd and Mo co-exposure on autophagy by nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant defense and endoplasmic reticulum stress (ERS) in duck livers, 40 healthy 7-day-old ducks were randomly assigned to 4 groups and fed diets containing different doses of Mo and/or Cd for 16 weeks, respectively. The results verified that Mo and/or Cd induced oxidative stress via decreasing glutathione peroxidase (GSH-Px), catalase (CAT), and total-superoxide dismutase (T-SOD) activities and increasing hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA) concentrations; inhibited Nrf2 axis by downregulating the pathway-related genes and proteins expression levels , and activated ERS through upregulating the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2a (eIF2a), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) pathway-related genes and proteins expression levels, which triggered autophagy via increasing autophagosomes , light chain 3 (LC3) puncta, LC3A, LC3B, autophagy-related gene 5 (Atg5), Bcl-2-interacting protein (Beclin-1) mRNA levels and Beclin-1, microtubule-associated protein light chain 3 II/I (LC3II/LC3I) protein levels, decreasing Dynein, p62 , mammalian target of rapamycin (mTOR) mRNA levels and p62 protein level. Additionally, the changes in Mo and Cd group were the most obvious. Briefly, our study reveals that autophagy induced by Mo and/or Cd may be associated with the activation of crosstalk between Nrf2-mediated antioxidant defense response and ERS in duck livers. Mo and Cd may aggravate toxic damage to the liver.
研究领域:
毒理学
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分子生物学
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兽医学
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PubMed
高影响因子
MOLECULES
·
2020
·Vol. 25
·期 22
·5302
·
IF 3.267
Lili Qin,Tianfeng Lu,Yao Qin,Yiwei He,Ningxin Cui,Ai Du,Jingyu Sun
Resveratrol (RSV) is a natural flavonoid polyphenol compound extracted from the plants which shows various biological activities. However, the clinical application of RSV is limited by its poor aqueous solubility, rapid metabolism and poor bioavailability. In this study, resveratrol-loaded solid lipid nanoparticles (RSV- SLNs) was design as a nano-antioxidant against the physical fatigue. The resultant RSV-SLNs were characterized by photon correlation spectroscopy (PCS), transmission electron micrographs (TEM), zeta potential, differential scanning calorimetry (DSC) and Raman spectroscopy pattern. Furthermore, the in vivo anti-fatigue effect assays showed that RSV-SLNs prolonged the mice exhausted time and running distance. The biochemical parameters of blood related to fatigue suggested that RSV-SLNs have potential applications to improve the antioxidant defense of the mice after extensive exercise and confer anti-fatigue capability. Furthermore, the molecular mechanisms of antioxidant by RSV-SLNs supplementation was investigated through the analysis of silent information regulator 2 homolog 1 (SIRT1) protein expression, which demonstrated that it could downregulate the expression of SIRT1 and increase autophagy markers, microtubule-associated protein 1 light chain 3-II (LC3-II) and sequestosome-1 (SQSTM1/p62). These results reveal that the RSV-SLNs may have great potential used as a novel anti-fatigue sports nutritional supplement.Keywords:solid lipid nanoparticles (SLNs);resveratrol;drug delivery;anti-fatigue;nutrition supplements
研究领域:
药理学
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纳米技术
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运动科学
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营养学
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PubMed
高影响因子
International Journal of Nanomedicine
·
2017
·
IF 4.3
QiHong Wu,RongRong Jin,Ting Feng,Li Liu,Li Yang,YuHong Tao,James M Anderson,Hua Ai,Hong Li
Superparamagnetic iron oxide nanoparticles have been widely used in biomedical applications, but understanding of their interactions with the biological immune system is relatively limited. This work is focused on dextran-coated iron oxide nanoparticles and their induced autophagy in human monocytes. We found that these nanoparticles can be taken up by human monocytes, followed by localization within vesicles or free in cytoplasm. Autophagosome formation was observed with increased expression of LC3II protein, the specific marker of autophagy. The autophagy substrate p62 was degraded in a dose-dependent manner, and autophagy was blocked by autophagy (or lysosome) inhibitors alone or along with iron oxide nanoparticles, indicating that autophagosome accumulation was mainly due to autophagy induction, rather than blockade of autophagy flux. Interestingly, iron oxide nanoparticles increased the viability of human monocytes, but the mechanism was not clear. We further found that inhibition of autophagy mostly attenuated the survival of cells, with acceleration of the inflammation induced by these nanoparticles. Taken together, autophagic activation in human monocytes may play a protective role against the cytotoxicity of iron oxide nanoparticles.
研究领域:
纳米技术
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免疫学
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细胞生物学
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PubMed
高影响因子
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