Cell Proliferation[JOURNAL]
Sun
200 papers
Mechanism of EC-EXOs-Derived THBS3 Targeting CD47 to Regulate BMSCs Differentiation to Ameliorate Bone Loss.
Wang J, Zhou Z, Chen W … +6 more , Chen Y, Zheng Q, Chen Y, Ouyang Z, Xu R, Lu Q
Cell Prolif · 2025 Dec · PMID 40514348 · Full text
With the continuous increase of the elderly population and the deepening of population ageing in China, osteoporosis has gradually become one of the significant public health problems. Elucidating the pathophysiological...
With the continuous increase of the elderly population and the deepening of population ageing in China, osteoporosis has gradually become one of the significant public health problems. Elucidating the pathophysiological mechanisms that induce osteoporosis and identifying more effective therapeutic targets is of great clinical significance. In this study, in vitro experiments demonstrated that endothelial cell exosomes (EC-EXOs) promoted osteogenic and inhibited adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Aged and ovariectomy (OVX)-induced osteoporosis mice models injected with EC-EXOs confirmed that EC-EXOs delayed bone loss. Proteomic analysis revealed a key protein regulating the differentiation of BMSCs. Expression of THBS3 was significantly higher in EC-EXOs than in Human microvascular endothelial cells (HMEC-1). In vitro and in vivo experiments further validated that THBS3 promoted BMSCs' osteogenic differentiation, inhibited their adipogenic differentiation, and retarded bone loss. Computational biology analysis found that CD47 is a downstream target and potentially functional receptor in BMSCs that bind to THBS3. THBS3 treatment of BMSCs down-regulated the expression of CD47 in in vitro experiments. The aged/OVX models further confirmed that EC-EXOs can regulate the differentiation of BMSCs and delay the process of bone loss via the THBS3-CD47 axis. CD47 antibody may be a potential therapeutic agent for treating ageing-associated bone loss.
FAM20C Modulates Neuronal Differentiation in Hypoxic-Ischemic Brain Damage via KAP1 Phosphorylation and LINE1 RNA m6A-Dependent H3K9me3 Regulation.
Feng CX, Wang M, Li G … +6 more , Chu SJ, Wu D, Hu XH, Xu LX, Li M, Feng X
Cell Prolif · 2026 Jan · PMID 40511628 · Full text
Neurodevelopmental impairment due to hypoxic-ischemic brain damage (HIBD) lacks effective biomarkers and therapeutic targets. Based on some cues from published papers, extracellular serine/threonine protein kinase FAM20C...
Neurodevelopmental impairment due to hypoxic-ischemic brain damage (HIBD) lacks effective biomarkers and therapeutic targets. Based on some cues from published papers, extracellular serine/threonine protein kinase FAM20C was speculated to play a crucial role in the neurodevelopmental impairment of HIBD. In this study, FAM20C was found suppressed in the ischemic hippocampal tissue of HIBD. The inhibition of FAM20C caused by HIBD affected cell differentiation and subsequently caused cognitive impairment. KAP1 was identified as a kinase substrate of FAM20C in the central nervous system. The regulation of the YTHDC1-NCL-KAP1-LINE1 RNA complex by FAM20C was mediated through KAP1 phosphorylation and LINE1 RNA m6A. These alterations consequently modulated the establishment of the H3K9me3 modification on LINE1 DNA, thereby resulting in neuronal differentiation. Furthermore, E2F4, identified as a transcription factor, regulated FAM20C in HIBD. This research has clarified the novel association between FAM20C and HIBD, laying the foundation for innovative diagnostic and therapeutic strategies to counteract neurodevelopmental disruptions arising from neonatal hypoxic-ischemic encephalopathy (HIE).
Tryptophan Suppresses FTH1-Driven Ferritinophagy, a Key Correlate of Prognosis in Hepatocellular Carcinoma.
Cheng X, Ge X, Zhang C … +8 more , Yang X, Yu Z, Zhang M, Cao W, Ni Q, Liu Y, He S, Yuan Y
Cell Prolif · 2026 Jan · PMID 40504108 · Full text
Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. Ferritinophagy, an autophagy-dependent process regulating iron metabolism, has emerged as a key contributor to ferroptosis and...
Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. Ferritinophagy, an autophagy-dependent process regulating iron metabolism, has emerged as a key contributor to ferroptosis and tumour progression. This study hypothesised that the ferritinophagy-related gene FTH1 drives HCC pathogenesis by modulating tryptophan metabolism and reactive oxygen species (ROS)-dependent ferroptosis. To test this, we first analysed TCGA data to identify prognostic ferritinophagy genes, revealing FTH1 as a critical risk factor. Functional experiments using FTH1-knockdown/-overexpressing HCC cell lines and xenograft models demonstrated that FTH1 enhances proliferation, migration, and tumour growth by upregulating CYP1A1/CYP1A2 in the tryptophan pathway, thereby increasing the synthesis of 6-hydroxymelatonin (6-HMT). Mechanistically, 6-HMT suppressed ROS and ferroptosis by inhibiting cytochrome P450 oxidoreductase (POR). Concurrently, intracellular tryptophan levels were found to inhibit NCOA4-mediated selective autophagy of FTH1, stabilising FTH1 levels and promoting tumour survival. Collectively, our findings establish FTH1 as a central regulator of ferritinophagy in HCC and reveal its dual role in linking tryptophan metabolism to redox homeostasis. This result provides a hint of how FTH1 influences HCC pathogenesis and positions the tryptophan metabolism pathway as a promising therapeutic target.
RNF219 RING Finger Domain Mutants Drive Phase Separation to Encapsulate CCR4-NOT and Promote Cell Proliferation.
Chen C, Guo C, Fang K … +2 more , Lin C, Luo Z
Cell Prolif · 2026 Jan · PMID 40497348 · Full text
RING finger protein 219 (RNF219) is a co-factor for the CCR4-NOT deadenylase complex in mammals. Here, we found that mutations within the C3HC4 scaffold of the RING finger domain in RNF219 are capable of forming condensa...
RING finger protein 219 (RNF219) is a co-factor for the CCR4-NOT deadenylase complex in mammals. Here, we found that mutations within the C3HC4 scaffold of the RING finger domain in RNF219 are capable of forming condensates via liquid-liquid phase separation (LLPS), though the wild-type RING finger domain intrinsically suppresses LLPS. We further demonstrated that the adjacent coiled-coil 1 (CC1) domain promotes the potential of RNF219 to form condensates. Moreover, the mutant RNF219 condensates are able to encapsulate the CCR4-NOT complex, inhibiting the RNA deadenylation activity of CCR4-NOT. Additionally, we observed that RNF219 mutations could promote cell proliferation. These findings suggest a pathogenic mechanism whereby RNF219 mutations could induce CCR4-NOT condensate formation, inhibit deadenylation-dependent mRNA decay and drive cell proliferation.
Role of Histone Deacetylase and Inhibitors in Cardiovascular Diseases.
Zhang LY, Wang YY, Wen R … +2 more , Zhang TN, Yang N
Cell Prolif · 2025 Dec · PMID 40497340 · Full text
Histone deacetylase(HDAC) is Zn-dependent histone deacetylases that regulate the key signalling pathways involved in gene transcription. 11 isoforms have been identified. Recent in vitro and in vivo studies have shown th...
Histone deacetylase(HDAC) is Zn-dependent histone deacetylases that regulate the key signalling pathways involved in gene transcription. 11 isoforms have been identified. Recent in vitro and in vivo studies have shown that HDACs are involved in the pathophysiology of cardiovascular diseases (CVDs) and play important roles in cell proliferation, differentiation and mitochondrial metabolism. In terms of physiological mechanisms, HDAC1-6 may play important roles in normal cardiac development and physiological function, while HDAC7 regulates angiogenesis. In pathological processes, class I HDACs function as pro-hypertrophic mediators, whereas class II HDACs act as anti-hypertrophic mediators. HDAC1-3, 6, 9, and 11 participate in lipid cell formation, oxidative stress and endothelial cell injury through multiple signalling pathways, contributing to the pathogenesis of atherosclerosis. In addition, HDACs also play a role in CVDs such as heart failure, myocardial fibrosis, pulmonary hypertension and diabetic cardiomyopathy. In view of this, we reviewed the regulatory pathways and molecular targets of HDACs in the pathogenesis of CVD. In addition, we summarise the current discovery of inhibitors targeting HDACs. HDAC inhibitors have shown promising therapeutic progress in animal experiments, but clinical trials to demonstrate their efficacy in humans are still lacking. A better understanding of the role of HDACs in CVD provides a new direction for the development of therapeutic interventions and holds significant research value.
Herbal Medicine for Colorectal Cancer Treatment: Molecular Mechanisms and Clinical Applications.
Su Z, Li Y, Zhou Z … +3 more , Feng B, Chen H, Zheng G
Cell Prolif · 2025 Oct · PMID 40488304 · Full text
Colorectal cancer (CRC) is one of the most common malignant tumours and is the second leading cause of cancer-related mortality worldwide. Despite the availability of preventative, diagnostic and treatment methods includ...
Colorectal cancer (CRC) is one of the most common malignant tumours and is the second leading cause of cancer-related mortality worldwide. Despite the availability of preventative, diagnostic and treatment methods including endoscopic treatment, surgical intervention, radiotherapy, biologics, salvage therapy and immunotherapy, the mortality rate associated with CRC remains alarming. Consequently, there is a pressing need to search for medicines for the treatment of CRC. Phytomedicines have been shown to suppress the proliferation and metastasis of CRC through various mechanisms, including immune regulation, modulation of gut microbiota, targeting of stem cells, macrophage polarisation, glycolysis, ferroptosis induction, modulation of extracellular vesicles, activation of mitochondria-induced apoptosis, inflammation reduction, oxidative stress management and intervention of autophagy. Furthermore, numerous studies have reported the anti-cancer and anti-metastatic effects of various phytomedicines, including curcumin, resveratrol, berberine, shikonin, dihydroartemisinin, fucoidan, luteolin, andrographolide, piperine, kaempferol, emodin, cannabidiol, tanshinone IIA and evodiamine. In this review, we sort out the effects and mechanisms of phytomedicines on CRC and outline the major phytomedicines commonly used in CRC treatment. We hope that these phytomedicines may serve as promising drugs or important lead compounds for the management of CRC.
Macrophage Efferocytosis as a Therapeutic Strategy in Intervertebral Disc Degeneration.
Chen S, Zhang H, Wang Z … +7 more , Zhu D, Li Y, Zhang Y, Wang D, Chen S, Liu H, Kang X
Cell Prolif · 2025 Oct · PMID 40488295 · Full text
In recent years, a growing number of studies have disclosed the substantial role of macrophages-key immune cells-in the pathological process of intervertebral disc degeneration. Researchers have categorised macrophage ph...
In recent years, a growing number of studies have disclosed the substantial role of macrophages-key immune cells-in the pathological process of intervertebral disc degeneration. Researchers have categorised macrophage phenotypes into M1 and M2 polarisation, associating these polarisations with intervertebral disc degeneration. Essentially, macrophage phenotypes can be classified as either pro-inflammatory or anti-inflammatory. Induced by diverse factors, these distinct polarisation states exert contrary effects on disc injury and repair. Although numerous studies focus on the polarisation of macrophages and the cytokines they secrete in relation to intervertebral disc degeneration, these studies frequently neglect the relationship between the efferocytosis of macrophages and the progression of intervertebral disc degeneration. Efferocytosis is a specialised procedure in which phagocytes, such as macrophages, engulf and eliminate apoptotic cells. This process is crucial for maintaining tissue homeostasis and resolving inflammation. By effectively clearing these dying cells, efferocytosis helps prevent the release of potentially detrimental cellular contents, thereby facilitating healing and the resolution of inflammation. Simultaneously, macrophages digest the engulfed cell debris and release various cytokines that participate in tissue self-repair. Therefore, this article presents an overview of the molecular mechanisms connecting macrophages and their efferocytosis activity to intervertebral disc degeneration, explores new directions for the utilisation of macrophages in the treatment of intervertebral disc degeneration, and discusses the future prospects for the development of therapeutic targets.
Neural Organoids Protect Engineered Heart Tissues From Glucolipotoxicity by Transferring Versican in a Co-Culture System.
Bai B, Li J, Wang Z … +20 more , Yang Y, He J, Chen G, Zhang Y, Qi Y, Wan Z, Cai L, Wang R, Wang K, Zhao D, Zhang J, Huang W, Xu RX, Sun M, Han X, Liu Y, Zhang D, Zhu W, Liu J, Guo Y
Cell Prolif · 2026 Jan · PMID 40459298 · Full text
Metabolic disorders could cause dysregulated glucose and lipid at the systemic level, but how inter-tissue/organ communications contribute to glucolipotoxicity is difficult to dissect in animal models. To solve this prob...
Metabolic disorders could cause dysregulated glucose and lipid at the systemic level, but how inter-tissue/organ communications contribute to glucolipotoxicity is difficult to dissect in animal models. To solve this problem, myocardium and nerve tissues were modelled by 3D engineered heart tissues (EHTs) and neural organoids (NOs), which were co-cultured in a generalised medium with normal or elevated glucose/fatty acid contents. Morphology, gene expression, cell death and functional assessments detected no apparent alterations of EHTs and NOs in co-culture under normal conditions. By contrast, NOs significantly ameliorated glucolipotoxicity in EHTs. Transcriptomic and protein secretion assays identified the extracellular matrix protein versican as a key molecule that was transferred from NOs into EHTs in the high-glucose/fatty acid condition. Recombinant versican protein treatment was sufficient to reduce glucolipotoxicity in EHTs. Adeno-associated virus-delivered versican overexpression was sufficient to ameliorate cardiac dysfunction in a murine model of diabetic cardiomyopathy. These data provide the proof-of-concept evidence that inter-tissue/organ communications exist in the co-culture of engineered tissues and organoids, which could be systemically studied to explore potential pathological mechanisms and therapeutic strategies for multi-organ diseases in vitro.
The Neuroprotective Role of Ginsenoside Rg1 Against Cerebral Ischemia-Reperfusion Damage Through Inhibition of Mitophagy via Blocking Mitophagosome-Lysosome Fusion.
Ai L, Ren H, Wang Y … +9 more , Liu M, Qiu Y, Feng J, Dai R, Fu W, Wang Y, Xi Z, Xu H, Wang F
Cell Prolif · 2026 Jan · PMID 40458031 · Full text
Ginsenoside Rg1 has shown promise in ameliorating cerebral ischemia-reperfusion injury (CIRI). However, its precise molecular mechanisms remain unclear. In this study, an in vitro CIRI model was established using SH-SY5Y...
Ginsenoside Rg1 has shown promise in ameliorating cerebral ischemia-reperfusion injury (CIRI). However, its precise molecular mechanisms remain unclear. In this study, an in vitro CIRI model was established using SH-SY5Y and SK-N-AS neuronal cell lines subjected to oxygen-glucose deprivation followed by reoxygenation (OGD/R). For the in vivo model, C57BL/6J mice underwent middle cerebral artery occlusion and subsequent reperfusion (MCAO/R). The protective effects of Rg1 against OGD/R injury were analysed using the CCK-8 assay and the PI exclusion method. The in vivo neuroprotective effects of Rg1 against CIRI were evaluated using various assessments, including brain blood flow, neurological deficits, behavioural tests, TTC, H&E, Nissl and TUNEL staining. Mitophagy was assessed by detecting mitophagy-initiating proteins via Western blotting, transmission electron microscopy, immunohistochemistry and immunofluorescence staining. Additionally, mitochondrial function was assessed by ATP measurement, the JC-1 assay and MitoSOX-based flow cytometry. Our results show that Rg1 significantly mitigated cell death caused by OGD/R and substantially enhanced cell viability in vitro. Moreover, Rg1 alleviated OGD/R-induced mitochondrial dysfunction, as indicated by preserved mitochondrial membrane potential and decreased mitochondrial ROS levels. Mitophagy was induced after OGD treatment, which was subsequently inhibited by Rg1 during reperfusion. Mechanistically, Rg1 disrupted the fusion of mitophagosomes with lysosomes rather than inhibiting mitophagy initiation, leading to an accumulation of mitochondrial proteins and mitophagy-initiating proteins. Notably, prolonged inhibition of mitophagy by Rg1 did not induce cytotoxicity or exacerbate mitochondrial dysfunction. Furthermore, administration of Rg1 in MCAO/R mice significantly improved brain blood reperfusion, reduced infarct volume, improved neurological deficits, preserved brain tissue integrity and decreased neuronal apoptosis. Consistent with the in vitro observations, Rg1 upregulated mitophagy-related protein expression in MCAO/R mouse brain tissues, indicating potential inhibition of mitophagy. In conclusion, our study reveals that Rg1 significantly alleviates CIRI at least partially by suppressing mitophagy, specifically by impeding the fusion of mitophagosomes with lysosomes.
Mechanotransduction Mediated by PDLIM5: The Critical Role of Serpin E2/Integrin β3-Cytoskeleton-Nucleoskeleton Axis in Mechanical Osteogenic Programming.
Yang Y, Wu S, Wang Y … +11 more , Tang J, Liu J, Wang J, Li Y, Khan AU, Khan MA, Liu W, Zhu J, Hu K, Dai J, Ouyang J
Cell Prolif · 2025 Dec · PMID 40457949 · Full text
Despite the regenerative and self-repair capabilities of bone tissues, significant bone loss can result in substantial bone defects. This study was aimed at investigating the role and underlying mechanisms of the mechano...
Despite the regenerative and self-repair capabilities of bone tissues, significant bone loss can result in substantial bone defects. This study was aimed at investigating the role and underlying mechanisms of the mechanosensitive protein PDZ and LIM Domain 5 (PDLIM5) in the osteogenic differentiation of human adipose-derived stem cells (hASCs) under cyclic tensile stress conditions relevant to bone tissue repair. Utilising proteomics and single-cell RNA sequencing, we identified PDLIM5 and serpin E2 as key genes associated with the osteogenic differentiation of stem cells. To evaluate the expression levels of these genes and related proteins, we utilised western blotting, immunofluorescence and alkaline phosphatase (ALP) staining. Furthermore, lentiviral transfection, Cell Counting Kit-8 (CCK-8) assays, transwell migration assays, wound healing assays and protein-protein interaction analyses were conducted to evaluate changes in osteogenic differentiation under both chemical and physical stimuli, as well as to explore the relationship between serine protease inhibitor E2 (serpin E2) and its downstream effector, PDLIM5. The interactions among serpin E2, integrin β3 and PDLIM5 were confirmed through Haematoxylin and Eosin (H&E) staining, immunohistochemistry and immunofluorescence staining of bone tissues and primary adipose-derived stem cells isolated from integrin β3 knockout mice. Our findings indicate that PDLIM5 modulates the osteogenic differentiation of hASCs via a signalling pathway involving serpin E2, integrin β3 and lamin A.
Repetitive Transcranial Magnetic Stimulation Induces Cognitive Recovery in Alzheimer's Disease via GABAergic Neuron Activation of the Cx3cl1-Cx3cr1 Axis.
Kang Y, Liu J, Wang Y … +5 more , Wang J, Wang J, Zhou C, Cui R, Zhang T
Cell Prolif · 2025 Dec · PMID 40415257 · Full text
This study aimed to investigate the impact of repetitive transcranial magnetic stimulation (rTMS) on cognitive recovery in Alzheimer's disease (AD) by exploring the role of GABAergic neuron activation and modulation of t...
This study aimed to investigate the impact of repetitive transcranial magnetic stimulation (rTMS) on cognitive recovery in Alzheimer's disease (AD) by exploring the role of GABAergic neuron activation and modulation of the Cx3cl1-Cx3cr1 signalling axis. The 5xFAD mouse model was utilised for scRNA-seq analysis to examine changes in gene expression post-rTMS. Microglial phagocytic activity, amyloid plaque burden, cell-cell communication, microglial morphology and neuroinflammation markers were assessed. Following rTMS, upregulation of Cx3cl1 in GABAergic neurons was observed, leading to enhanced microglial phagocytosis, reduced amyloid plaque burden, improved cell-cell communication, altered microglial morphology and decreased neuroinflammation markers. This study demonstrates that rTMS promotes Aβ clearance and cognitive recovery in AD by activating GABAergic neurons and enhancing Cx3cl1-Cx3cr1 signalling, providing a novel molecular target for non-invasive AD therapy. These findings support the transition from invasive to non-invasive AD treatments, improving patient adherence and therapeutic outcomes. Furthermore, the elucidation of cellular and molecular mechanisms facilitates drug development targeting the Cx3cl1-Cx3cr1 axis, offering new opportunities for AD intervention.
Deficiency of Aging-Related Gene Chitinase-Like 4 Impairs Olfactory Epithelium Homeostasis.
Wu T, Li W, Zhuang L … +5 more , Liu J, Wang P, Gu Y, Liu Y, Yu Y
Cell Prolif · 2025 Aug · PMID 40389328 · Full text
Mammalian olfactory epithelium (OE) undergoes consistent self-renewal throughout life. In OE homeostasis, globose basal cells (GBCs) contribute to the generation of olfactory sensory neurons (OSNs) to replace old ones. C...
Mammalian olfactory epithelium (OE) undergoes consistent self-renewal throughout life. In OE homeostasis, globose basal cells (GBCs) contribute to the generation of olfactory sensory neurons (OSNs) to replace old ones. Chitinase-like 4 (Chil4), a chitinase-like protein expressed in supporting cells, plays a critical role in OE regeneration, while its role in tissue homeostasis is still elusive. Here, we found that Chil4 is upregulated in the aged OE. Deletion of Chil4 leads to a reduction in the number of GBCs and immature OSNs (iOSNs). Chil4 GBCs show attenuation in cell cycle progression and an aberrant expression pattern of cell-cycle-related genes such as Cdk1. Chil4 deletion causes loss of a specific subcluster of GAP43 iOSNs expressing Cebpb, Nqo1 and low level of mature OSN (mOSN) marker Stoml3 (iOSN_CeStNq), potentially suggesting a transitional state between immature and mature neurons. Chil4 knockout induces inflammatory activation in Iba1 microglia (MG)-like cells in the OE. Chil4 downregulation in aged organoids reduced the number of mature sensory neurons, suggesting a necessary role of Chil4 in maintaining neuronal generation in the aged OE. Collectively, these observations reveal a previously unidentified function of Chil4, establishing the cellular mechanism underlying OE homeostasis.
Engineering Intervertebral Disc Regeneration: Biomaterials, Cell Sources and Animal Models.
Yang S, Soheilmoghaddam F, Pivonka P … +6 more , Li J, Rudd S, Yeo T, Tu J, Zhu Y, Cooper-White JJ
Cell Prolif · 2025 Sep · PMID 40389238 · Full text
Intervertebral disc (IVD) degeneration is an age-related problem triggering chronic spinal issues, such as low back pain and IVD herniation. Standard surgical treatment for such spinal issues is the removal of the degene...
Intervertebral disc (IVD) degeneration is an age-related problem triggering chronic spinal issues, such as low back pain and IVD herniation. Standard surgical treatment for such spinal issues is the removal of the degenerated or herniated IVD and fusion of adjacent vertebrae to stabilise the joint and locally decompress the spinal cord and/or nerve roots to relieve pain. However, a key challenge of current surgical strategies is the increasing risk of adjacent segment degeneration due to the disruption of native biomechanics of the functional spinal unit, dominated by the loss of the IVD. In the past two decades, research has focused on developing a number of bioengineering approaches to repair and regenerate the IVD; in particular, tissue engineering of the IVD, using bioscaffolds and stem cells represents a promising area. This review highlights the current tissue engineering approaches utilising biomaterials, animal models and cell sources for IVD regeneration and discusses future opportunities.
Ellagic Acid-Loaded sEVs Encapsulated in GelMA Hydrogel Accelerate Diabetic Wound Healing by Activating EGFR on Skin Repair Cells.
Tian L, Wang Z, Chen S … +9 more , Guo K, Hao Y, Ma L, Ma K, Chen J, Liu X, Li L, Fu X, Zhang C
Cell Prolif · 2025 Oct · PMID 40384373 · Full text
Delayed diabetic wound healing is partially attributed to the functional disorder of skin repair cells caused by high glucose (HG). Small extracellular vehicles (sEVs) loaded with small-molecule drugs represent a highly...
Delayed diabetic wound healing is partially attributed to the functional disorder of skin repair cells caused by high glucose (HG). Small extracellular vehicles (sEVs) loaded with small-molecule drugs represent a highly promising therapeutic strategy. This study aims to evaluate the therapeutic efficacy of ellagic acid-encapsulated small extracellular vesicles (EA-sEVs) in diabetic wound regeneration and to unravel related mechanisms. Cytotoxicity tests of ellagic acid (EA) as liposomal small molecules (LSMs) were performed with the CCK8 assay. EA was incorporated into sEVs obtained from chorionic plate-mesenchymal stem cells (CP-MSCs) to construct EA-engineered sEVs. The protective effects of EA-sEVs on human dermal fibroblasts (HDFs) and human epidermal keratinocytes (HEKs) induced by high glucose (HG) were assessed through the evaluation of their proliferative, migrative and differentiative capabilities. Furthermore, to illustrate the underlying mechanism, the specific biological targets of EA were predicted and confirmed. Finally, EA-sEVs were encapsulated in GelMA hydrogel for investigating the pro-healing effects on diabetic wounds. EA was harmless to cell viability, increasing the possibility and safety of drug development. EA-engineered sEVs were fabricated by loading EA in sEVs. In vitro, EA-sEVs promoted the proliferation, migration, and transdifferentiation of HG-HDFs and the proliferation and migration of HG-HEKs. Mechanism analysis elucidated that epidermal growth factor receptor (EGFR) was the specific biological target of EA. EA interacting with EGFR was responsible for the functional improvement of HG-HDFs and HG-HEKs. In vivo, EA-sEVs encapsulated in GelMA promoted the healing of diabetic wounds by improving re-epithelialisation, collagen formation and the expression of EGFR. Gel-EA-sEVs promoted diabetic wound healing by improving biological functions of HDFs and HEKs. EGFR was first identified as the specific biological target of EA and was responsible for the functional improvement of HG-HDFs and HG-HEKs by Gel-EA-sEVs. Hence, Gel-EA-sEVs can serve as a new promising active dressing for diabetic wound treatment.
Deciphering the Immunomodulatory Function of GSN Inflammatory Cancer-Associated Fibroblasts in Renal Cell Carcinoma Immunotherapy: Insights From Pan-Cancer Single-Cell Landscape and Spatial Transcriptomics Analysis.
Li S, Zhou X, Feng H … +16 more , Huang K, Chen M, Lin M, Lin H, Deng Z, Chen Y, Liao W, Zhang Z, Chen J, Guan B, Su T, Feng Z, Shu G, Yu A, Pan Y, Fu L
Cell Prolif · 2025 Dec · PMID 40375605 · Full text
The heterogeneity of cancer-associated fibroblasts (CAFs) could affect the response to immune checkpoint inhibitor (ICI) therapy. However, limited studies have investigated the role of inflammatory CAFs (iCAFs) in ICI th...
The heterogeneity of cancer-associated fibroblasts (CAFs) could affect the response to immune checkpoint inhibitor (ICI) therapy. However, limited studies have investigated the role of inflammatory CAFs (iCAFs) in ICI therapy using pan-cancer single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics sequencing (ST-seq) analysis. We performed pan-cancer scRNA-seq and ST-seq analyses to identify the subtype of GSN iCAFs, exploring its spatial distribution characteristics in the context of ICI therapy. The pan-cancer scRNA-seq and bulk RNA-seq data are incorporated to develop the Caf.Sig model, which predicts ICI response based on CAF gene signatures and machine learning approaches. Comprehensive scRNA-seq analysis, along with in vivo and in vitro experiments, investigates the mechanisms by which GSN iCAFs influence ICI efficacy. The Caf.Sig model demonstrates well performances in predicting ICI therapy response in pan-cancer patients. A higher proportion of GSN iCAFs is observed in ICI non-responders compared to responders in the pan-cancer landscape and clear cell renal cell carcinoma (ccRCC). Using real-world immunotherapy data, the Caf.Sig model accurately predicts ICI response in pan-cancer, potentially linked to interactions between GSN iCAFs and CD8 Tex cells. ST-seq analysis confirms that interactions and cellular distances between GSN iCAFs and CD8 exhausted T (Tex) cells impact ICI efficacy. In a co-culture system of primary CAFs, primary tumour cells and CD8 T cells, downregulation of GSN on CAFs drives CD8 T cells towards a dysfunctional state in ccRCC. In a subcutaneously tumour-grafted mouse model, combining GSN overexpression with ICI treatment achieves optimal efficacy in ccRCC. Our study provides the Caf.Sig model as an outperforming approach for patient selection of ICI therapy, and advances our understanding of CAF biology and suggests potential therapeutic strategies for upregulating GSN in CAFs in cancer immunotherapy.
LL-37 Inhibits TMPRSS2-Mediated S2' Site Cleavage and SARS-CoV-2 Infection but Not Omicron Variants.
Bi Z, Ren W, Zeng H … +8 more , Zhou Y, Liu J, Chen Z, Zhang X, He X, Lu G, Wei Y, Wei X
Cell Prolif · 2025 Dec · PMID 40375579 · Full text
Continual evolution of SARS-CoV-2 spike drives the emergence of Omicron variants that show increased spreading and immune evasion. Understanding how the variants orientate themselves towards host immune defence is crucia...
Continual evolution of SARS-CoV-2 spike drives the emergence of Omicron variants that show increased spreading and immune evasion. Understanding how the variants orientate themselves towards host immune defence is crucial for controlling future pandemics. Herein, we demonstrate that human cathelicidin LL-37, a crucial component of innate immunity, predominantly binds to the S2 subunit of SARS-CoV-2 spike protein, occupying sites where TMPRSS2 typically binds. This binding impedes TMPRSS2-mediated priming at site S2' and subsequent membrane fusion processes. The mutation N764K within S2 subunit of Omicron variants reduces affinity for LL-37 significantly, thereby diminishing binding capacity and inhibitory effects on membrane fusion. Moreover, the early humoral immune response enhanced by LL-37 is observed in mice against SARS-CoV-2 spike but not Omicron BA.4/5 spike. These findings reveal the mechanism underlying interactions amongst LL-37, TMPRSS2 and SARS-CoV-2 and VOCs, and highlight the distinct mutation for Omicron variants to evade the fusion activity inhibition by host innate immunity.
Regulating the Plasticity of Hippocampal Neurons via Electroacupuncture in Depression Model Mice.
Wang Y, Du X, Duan C … +5 more , Wang M, Zhu Y, Wang L, Hu J, Sun Y
Cell Prolif · 2025 Oct · PMID 40374592 · Full text
Effective treatment of depression poses a major clinical challenge, accompanied by considerable social and emotional burdens. Electroacupuncture, a non-pharmacological modality derived from traditional Chinese medicine,...
Effective treatment of depression poses a major clinical challenge, accompanied by considerable social and emotional burdens. Electroacupuncture, a non-pharmacological modality derived from traditional Chinese medicine, offers a promising alternative for depression treatment due to its safety and efficacy. However, its underlying molecular mechanisms remain unclear. In this study, a corticosterone-induced depression model in C57BL/6 mice was employed and electroacupuncture was applied to stimulate at Zusanli (ST36) acupoint. The results demonstrated that electroacupuncture effectively alleviated depression-like symptoms and restored the structural morphology and plasticity of neurons in the hippocampal CA1 region. Further analysis revealed a significant upregulation of brain-derived neurotrophic factor (BDNF) and β-type calmodulin-dependent protein kinase II (CaMKIIβ), which are associated with neuronal plasticity regulatory pathways. This study elucidates the potential molecular mechanisms by which electroacupuncture alleviates depression through the regulation of neuroplasticity, providing an experimental basis for its clinical application.
Nano-Mediated Fluorescence Switching for Epidermal Growth Factor Receptor Detection.
Fu X, Wang Y, Zhang W … +9 more , Yang Y, Zeng J, Li X, Feng C, Li B, Liu Y, Zhang Y, Zhang C, Ma S
Cell Prolif · 2025 Dec · PMID 40368641 · Full text
Identification of the epidermal growth factor receptor (EGFR) in biological specimens is essential for cancer diagnostics, drug development and therapeutic monitoring. However, real-time techniques for accurate EGFR expr...
Identification of the epidermal growth factor receptor (EGFR) in biological specimens is essential for cancer diagnostics, drug development and therapeutic monitoring. However, real-time techniques for accurate EGFR expression monitoring are currently limited. In this study, we report the development of a novel nano detector (Cy3-Apt@BPNSs) with the capabilities of quenching and recovery to enable visual EGFR expression analysis. Cy3-Apt is a Cy3-labelled single-stranded RNA (ssRNA) that exhibits specific binding to EGFR. Black phosphorus nanosheets (BPNSs) possess the ability to adsorb Cy3-Apt via van der Waals forces, quenching its fluorescence when combined. The detection of EGFR receptors on cancer cell surfaces prompts the release of Cy3-Apt from BPNSs, a consequence of the robust binding interaction between the receptor and aptamer, thereby leading to fluorescence reinstatement. The recovered fluorescence intensity of this detector is found to be directly correlated with EGFR expression levels in cancer cells, indicating its potential for guiding tumour diagnosis and treatment. The specificity of Cy3-Apt@BPNSs further enhances its utility in detecting EGFR. More importantly, our research demonstrates that the reduction in EGFR expression levels within cancer cells corresponds to a proportional decline in fluorescence intensity, thereby facilitating precise tracking of EGFR dynamics.
RBM39 Promotes Base Excision Repair to Facilitate the Progression of HCC by Stabilising OGG1 mRNA.
An H, Xia A, Liu S … +5 more , Luo D, Geng L, Li B, Sun B, Xu Z
Cell Prolif · 2025 Oct · PMID 40364450 · Full text
Targeting base excision repair (BER) has been an attractive strategy in cancer therapeutics. RNA-binding motif protein 39 (RBM39) modulates the alternative splicing of numerous genes involved in cancer occurrence and pro...
Targeting base excision repair (BER) has been an attractive strategy in cancer therapeutics. RNA-binding motif protein 39 (RBM39) modulates the alternative splicing of numerous genes involved in cancer occurrence and progression. However, whether and how RBM39 regulates BER in hepatocellular carcinoma (HCC) remain unclear. Here, we found that under oxidative stress, RBM39 degradation or knockdown decreased BER efficiency in HCC cells using a well-designed BER reporter. Further assays showed that RBM39 promoted HCC cell proliferation, migration, and invasion, enhancing cell survival and inhibiting apoptosis. Mechanistically, RBM39 interacted with the mRNA of the essential glycosidase 8-oxoguanine-DNA glycosylase 1 (OGG1), thereby stabilising OGG1 mRNA. This in turn increases OGG1 expression and promotes BER efficiency in HCC. Moreover, data suggested that RBM39 degradation, combined with oxidative damage, could be more effective for HCC treatment than monotherapy, both in vitro and in xenograft mice models. Overall, we demonstrated that RBM39 regulated OGG1 stabilisation and improved BER efficiency, suggesting that combining the RBM39 degradant indisulam with the oxidising agent KBrO could be an emerging strategy for HCC treatment.
NSun2-Mediated tsRNAs Alleviate Liver Fibrosis via FAK Dephosphorylation.
Li P, Ying S, Zou Y … +12 more , Wang X, Zhang R, Huang C, Dai M, Xu K, Feng G, Li X, Jiang H, Li Z, Zhang Y, Li W, Zhou Q
Cell Prolif · 2025 Oct · PMID 40355098 · Full text
Sinusoidal capillarization - key symptoms of liver fibrosis progression - represents potential therapeutic targets. tRNA modification-mediated tRNA-derived small RNAs (tsRNAs) play a role in angiogenesis. NSun2, an RNA m...
Sinusoidal capillarization - key symptoms of liver fibrosis progression - represents potential therapeutic targets. tRNA modification-mediated tRNA-derived small RNAs (tsRNAs) play a role in angiogenesis. NSun2, an RNA methyltransferase, generates a significant number of tsRNAs. However, the role of NSun2 and its mediated tsRNAs in liver fibrosis remains unclear. In this study, NSun2 deficiency was found to inhibit sinusoidal capillarization, alleviating liver fibrosis. Furthermore, endothelial cell angiogenesis and migration were disrupted in NSun2 knockout mice. Mechanistically, reduced NSun2 expression led to alterations in the functional tsRNAs tRF-1-S25 and tRF-5-V31, which regulate sinusoidal capillarization by targeting key proteins, including DUSP1 and FAK - crucial clinical targets. Moreover, intravenous injection of tRF-1-S25 and tRF-5-V31 inhibitor rescued liver fibrosis in mice. In conclusion, tsRNAs generated by NSun2-mediated modification of tRNAs inhibit sinusoidal capillarization. Furthermore, targeting the DUSP1/FAK/p-FAK pathway offers an innovative approach to treat this disease.
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