Cell Proliferation[JOURNAL]
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200 papers
Periodontitis-Associated Circulating EVs Promote Colorectal Cancer Progression via Carnosine-Mediated Acidosis Adaptation.
Wu R, Cai Z, Sun H … +13 more , Yu H, Zhang B, Zhang C, Fan Y, Zhu X, Ni Y, Cui Y, Wang K, Li Z, Zhou X, He Q, Wu Y, Zhang Y
Cell Prolif · 2026 Jul · PMID 42386523 · Publisher ↗
Colorectal cancer (CRC) is the third most common malignancy worldwide. Epidemiological studies have suggested a positive association between periodontitis (PD) and CRC risk; however, the mechanistic basis underlying this...
Colorectal cancer (CRC) is the third most common malignancy worldwide. Epidemiological studies have suggested a positive association between periodontitis (PD) and CRC risk; however, the mechanistic basis underlying this relationship remains unclear. Extracellular vesicles (EVs) represent an important mode of systemic communication and may mediate the distal effects between PD and CRC. PD model was established in Apc mice with spontaneous intestinal tumorigenesis. Tumour onset, burden, and progression were evaluated in the colorectum and small intestine. Circulating EVs were isolated from the plasma of PD or sham mice and characterised. The functional contribution of EVs was assessed using pharmacological inhibition of EV release and MC38 syngeneic tumour models. Metabolomic profiling, RNA sequencing, and in vitro functional assays were performed to investigate EV cargo and underlying mechanisms. PD significantly accelerated CRC onset and increased tumour number and size in Apc mice. Inhibition of EV release by GW4869 attenuated PD-driven tumour progression, indicating a critical role of periodontitis-associated EVs (PDEVs). PDEVs promoted tumour growth and induced an immunosuppressive tumour microenvironment in MC38 transplanted tumours. Metabolomic analysis revealed marked enrichment of carnosine in PDEVs. Under acidic conditions, EV-delivered carnosine alleviated intracellular acidosis, preserved lysosomal positioning and acidification, and promoted proliferation, migration, and epithelial-mesenchymal transition of MC38 cells. Collectively, circulating EV-mediated metabolic communication pathway linking PD to CRC progression. By delivering carnosine, PDEVs support malignant phenotypes and facilitate tumour adaptation to acidic stress. Circulating EV-associated carnosine may represent a potential biomarker and a candidate target for modulating CRC progression in high-risk populations.
PLIN5 Protects Against Ang II-Induced Podocyte Lipotoxicity by Interacting With FKBP8 and Preserving Lipid Droplet-Mitochondria Contact.
Wang P, Chen W, Ke J … +5 more , Hu H, Peng Z, Qi Y, Ding G, Hu J
Cell Prolif · 2026 Jun · PMID 42379659 · Publisher ↗
Chronic kidney disease (CKD) remains a major global health challenge. Angiotensin II (Ang II)-induced lipotoxicity is an important contributor to podocyte injury. Perilipin 5 (PLIN5) is a lipid droplet-associated protein...
Chronic kidney disease (CKD) remains a major global health challenge. Angiotensin II (Ang II)-induced lipotoxicity is an important contributor to podocyte injury. Perilipin 5 (PLIN5) is a lipid droplet-associated protein that helps maintain cellular metabolic homeostasis. However, how PLIN5 protects podocytes from lipotoxic stress remains incompletely understood. In this study, we generated podocyte-specific PLIN5 knockout mice using the Cre-loxP system and induced PLIN5 overexpression in vivo and in vitro. We found that Ang II markedly downregulated PLIN5 expression in podocytes both in vivo and in vitro. Podocyte-specific deletion of PLIN5 aggravated Ang II-induced lipid accumulation, mitochondrial dysfunction and apoptosis, whereas PLIN5 overexpression alleviated these abnormalities. Proteomic screening identified FK506-binding protein 8 (FKBP8), an outer mitochondrial membrane protein, as a PLIN5-interacting partner. Co-immunoprecipitation and proximity ligation assays showed that the PLIN5-FKBP8 interaction was reduced under Ang II stimulation. Functionally, FKBP8 knockdown disrupted lipid droplet-mitochondria contact and exacerbated Ang II-induced podocyte lipotoxicity. Domain-mapping and rescue experiments further demonstrated that the 70-200 amino acid region of FKBP8 is required for PLIN5 binding and for preservation of lipid droplet-mitochondria contact under lipotoxic stress. In addition, disruption of the PLIN5-FKBP8 axis was associated with impaired fatty acid utilisation and altered mitochondrial homeostasis. Collectively, these findings support a model in which PLIN5 protects podocytes, at least in part, by interacting with FKBP8 and preserving lipid droplet-mitochondria contact, thereby limiting Ang II-induced lipotoxic injury.
Unveiling Gut Homeostasis Disruption in Sepsis: Towards an Integrated Mechanistic and Translational Roadmap.
Bao Y, Qi L, Zou G … +5 more , Yang X, Ma Y, Li Z, Du X, Zhao P
Cell Prolif · 2026 Jun · PMID 42366111 · Publisher ↗
Sepsis, a life-threatening clinical syndrome precipitated by a maladaptive host response to infection, is associated with substantial morbidity and high mortality rates. Gastrointestinal injury has gained recognition as...
Sepsis, a life-threatening clinical syndrome precipitated by a maladaptive host response to infection, is associated with substantial morbidity and high mortality rates. Gastrointestinal injury has gained recognition as a pivotal factor driving sepsis progression. Pathogen invasion incites oxidative stress and inflammatory cascades, leading to compromised intestinal barrier integrity and dysregulated local immunity. This results in increased gut permeability and bacterial translocation, fostering a state that can be described as 'enteric sepsis'. Moreover, multi-organ crosstalk via the gut-liver and gut-brain axes substantially amplifies systemic inflammation. The pathophysiology of sepsis-induced intestinal injury is not yet fully elucidated, and clinically applicable biomarkers or early diagnostic tools remain scarce. Targeted therapeutic strategies have yet to be validated in clinical practice. This article presents a comprehensive review of recent advances in the pathophysiology and underlying mechanisms of sepsis-induced intestinal injury, focusing on the signalling networks that disrupt intestinal homeostasis and immune equilibrium. Particular emphasis is placed on identifying key pathways and candidate biomarkers for early diagnosis and intervention. Additionally, the therapeutic potential of targeted intestinal-protective agents is evaluated, integrating insights from traditional Chinese medicine to propose a combined treatment strategy. Ultimately, this review aims to establish a translational framework to advance clinical management and therapeutic innovation for sepsis-associated intestinal dysfunction.
The E-cadherin-Wnt-mir-994 Axis Repurposes a Cadherin Switch for Niche Robustness and Germline Stem Cell Maintenance.
Tu R, Yau HL, Deng R … +4 more , Webb SE, Chen S, Ni J, Xie T
Cell Prolif · 2026 Jun · PMID 42359497 · Publisher ↗
The resilience and robustness of the stem cell niche are critical for long-term tissue homeostasis, yet the molecular circuits that ensure this stability remain poorly understood. In the Drosophila ovarian germline stem...
The resilience and robustness of the stem cell niche are critical for long-term tissue homeostasis, yet the molecular circuits that ensure this stability remain poorly understood. In the Drosophila ovarian germline stem cell niche, we investigate this fundamental question through the lens of adhesion, focusing on the role of N-cadherin in the somatic inner germarial sheath (IGS) cells. While the specific loss of N-cadherin alone is inconsequential, we discover that it becomes essential upon the loss of E-cadherin, revealing a critical, context-dependent function. This functional interplay is governed by a precise molecular circuit wherein E-cadherin cell-autonomously represses N-cadherin expression via a linear Wnt-mir-994 signalling axis. Strikingly, this regulatory relationship constitutes a cadherin switch, which is repurposed within the niche not to promote dispersal, but to enforce resilience. The E-cadherin-to-N-cadherin switch acts as a vital compensatory mechanism: the ectopic upregulation of N-cadherin upon E-cadherin depletion is essential to maintain IGS cell survival and their long cellular processes, thereby rescuing niche integrity and preventing GSC loss. Our study defines the function for N-cadherin in IGS cells, unveils the E-cadherin-Wnt-mir-994-N-cadherin axis and demonstrates the repurposing of a classic developmental module as a robustness circuit to safeguard the stem cell niche. This repurposed cadherin switch reveals an axis for targeting the resilience of niche-stem cell interplay, and also informs new strategies for stabilizing niche environments in regenerative medicine or targeting the resilient cancer stem cell microenvironment.
A Multicellular Coordinated Network Driving Lymphovascular Space Invasion in Endometrioid Endometrial Carcinoma.
Guo W, Liu T, Ren R … +5 more , Li N, Zhang W, Si J, Piao Y, Hu Y
Cell Prolif · 2026 Jun · PMID 42336618 · Publisher ↗
Lymphovascular space invasion (LVSI) is a critical factor linked to metastasis and poor outcomes in endometrioid endometrial carcinoma (EEC), yet its multicellular mechanisms remain unclear. Using single-cell RNA sequenc...
Lymphovascular space invasion (LVSI) is a critical factor linked to metastasis and poor outcomes in endometrioid endometrial carcinoma (EEC), yet its multicellular mechanisms remain unclear. Using single-cell RNA sequencing of 3 LVSI-present (LVSI+) EECs, 2 LVSI-absent (LVSI-) EECs, and 2 normal endometrial samples, we delineated the cellular ecosystems underlying LVSI. LVSI+ EECs exhibited marked epithelial reprogramming, transitioning from differentiated ciliated epithelium to hyperproliferative and metabolically remodelled phenotypes, and contained TC4, a metastatic epithelial subset characterized by hypoxia, partial epithelial-mesenchymal transition, immunosuppression, and progesterone resistance. We also identified nine key genes in malignant epithelial cells associated with LVSI prognosis. The tumour microenvironment in LVSI+ EECs shifted from an inflammatory state dominated by epithelial cells to a collaborative network involving stromal and immune cells. This network was enriched in immunosuppressive ZNF683 + SOX4 + CD8+ T cells, Cycling_T cells, SPP1 + MMP9 + Mac, WNT5A_mCAF, Tip endothelial cells, and lymphatic endothelial cells. WNT5A_mCAF and SPP1 + MMP9 + Mac synergistically remodelled the extracellular matrix, promoted lymphangiogenesis and angiogenesis, and, together with endothelial cells, suppressed T-cell activity via LGALS9-HAVCR2/CD44 inhibitory signalling, thereby establishing a niche conducive to vascular invasion. Using spatial multiplex immunofluorescence, we confirmed hypoxic tumour epithelial cells at the invasive front coexisting with an immunosuppressive microenvironment, and revealed spatial colocalization of PD-L1+ tumour cells, PD-L1+ macrophages, and PD-1+ T cells within LVSI thrombi. Our comprehensive study provides deeper insights into LVSI as an actively coordinated multicellular process, potentially improving LVSI risk prediction, supporting treatment decision-making, and informing new therapies targeting the tumour microenvironment.
RETRACTION: Long Non-Coding RNA HCG11 Modulates Glioma Progression Through Cooperating With miR-496/CPEB3 Axis.
Cell Prolif · 2026 Jun · PMID 42332432 · Publisher ↗
Y. Chen, C. Bao, X. Zhang, X. Lin, H. Huang, and Z. Wang, "Long Non-Coding RNA HCG11 Modulates Glioma Progression Through Cooperating With miR-496/CPEB3 Axis," Cell Proliferation 52, no. 5 (2019): e12615, https://doi.org...
Y. Chen, C. Bao, X. Zhang, X. Lin, H. Huang, and Z. Wang, "Long Non-Coding RNA HCG11 Modulates Glioma Progression Through Cooperating With miR-496/CPEB3 Axis," Cell Proliferation 52, no. 5 (2019): e12615, https://doi.org/10.1111/cpr.12615. The above article, published online on 16 July 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Qi Zhou; and John Wiley & Sons Ltd. The retraction has been agreed following concerns raised by a third party. An investigation identified duplication of the Cyclin D1 bands in the western blot presented for the U87 cells in Figure 6C with bands published earlier in another article by a different group of authors. The duplicated bands were also used to represent a different protein. The authors did not respond to requests to address the concerns and did not provide the original data. The editors therefore consider the results and conclusions reported in this article to be unreliable. The authors did not respond to our notice of retraction.
Lactate-Primed NETosis Modulates Hepatic Regeneration During Acute Liver Failure via the TLR9/KLF15/AJUBA Axis.
Guo J, Zhang X, Zhang D … +3 more , Shi C, Wang L, Gong Z
Cell Prolif · 2026 Jun · PMID 42331029 · Publisher ↗
Acute liver failure (ALF) is characterised by massive hepatocyte death and compromised regenerative capacity, yet the metabolic-immune crosstalk underlying these pathological processes remains poorly understood. Here, we...
Acute liver failure (ALF) is characterised by massive hepatocyte death and compromised regenerative capacity, yet the metabolic-immune crosstalk underlying these pathological processes remains poorly understood. Here, we demonstrate that lactate acts as a pivotal signal that triggers neutrophil extracellular traps (NETs) formation and release. Integrated RNA-seq and scRNA-seq analyses revealed profound glycolytic reprogramming in Kupffer cells (KCs) during ALF, leading to lactate accumulation within the hepatic microenvironment. Mechanistically, neutrophils import exogenous lactate into mitochondria via monocarboxylate transporter 1 (MCT1), which subsequently activates NETosis. Macrophage depletion or administration of an MCT1 inhibitor reduced NETs formation and ameliorated liver injury. Furthermore, we demonstrate that hepatocytes internalise NETs DNA, which is sensed by endosomal Toll-like receptor 9 (TLR9). Activation of the TLR9 signalling pathway suppresses the expression of Krüppel-like factor 15 (KLF15). This downregulation diminishes AJUBA and disrupts the KLF15-AJUBA interaction, thereby increasing the phosphorylation of YAP1 and impeding hepatocyte proliferation. Notably, KLF15 overexpression bypassed TLR9-mediated inhibitory signals and rescued the NETs-induced regenerative failure in vitro. In conclusion, our study elucidates a novel KCs-neutrophil-hepatocyte crosstalk wherein lactate-driven NETosis thwarts liver regeneration via the TLR9/KLF15/AJUBA axis, thereby identifying potential therapeutic targets for the clinical management of ALF.
Ketogenic Diet Alleviates Colorectal Cancer by Attenuating Macrophage M2 Polarisation Triggered by Oncometabolite MMA Derived From the Gut Microbiota.
Lu Y, Shi B, Chen J … +11 more , Yao H, Mi X, Shao M, Zhao Y, Meng L, Tai Q, Chen J, Shi X, Zhou D, Yao Y, He S
Cell Prolif · 2026 Jun · PMID 42311078 · Publisher ↗
Proposed mechanism of the ketogenic diet-microbiota-MMA-immune axis in CRC. (Part 1) A ketogenic diet remodels gut microbiota homeostasis by depleting MMA-producing bacteria, thereby reducing the accumulation of the onco...
Proposed mechanism of the ketogenic diet-microbiota-MMA-immune axis in CRC. (Part 1) A ketogenic diet remodels gut microbiota homeostasis by depleting MMA-producing bacteria, thereby reducing the accumulation of the oncometabolite (MMA). (Part 2) At the molecular level, MMA acts as a ligand that binds to Rap1, activating the downstream MAPK/ERK signalling cascade. This signalling event drives the transcriptional reprogramming of TAMs towards the pro-tumorigenic M2 phenotype. (Part 3) Clinically, elevated serum MMA in CRC patients correlates with increased M2 macrophage infiltration in the tumour microenvironment and poor prognosis.
A 3D Bioprinted Platform That Maintains the Functional Integrity of Primary AML Cells.
Huang W, Deng B, Guo N … +8 more , Ding Y, Xu Z, Lu Y, Ma Y, Ren Q, Wang N, Huang P, Ma X
Cell Prolif · 2026 Jun · PMID 42303242 · Publisher ↗
Acute myeloid leukaemia (AML) urgently requires more reliable in vitro platforms for drug evaluation, as existing models often fail to maintain the phenotypic, metabolic, and pharmacologic features of primary leukaemic c...
Acute myeloid leukaemia (AML) urgently requires more reliable in vitro platforms for drug evaluation, as existing models often fail to maintain the phenotypic, metabolic, and pharmacologic features of primary leukaemic cells. To address this limitation, we developed a rapidly assembled, screening-compatible three-dimensional (3D) bioprinting platform. It encapsulates patient-derived bone marrow mononuclear cells within a gelatin-hyaluronic acid hydrogel, whose mechanical properties are tuned to match those of native bone marrow. Within this controlled 3D microenvironment, primary AML cells better maintain an in vivo-like state, showing enhanced viability, sustained proliferative capacity, preservation of stem-like subpopulations, and drug responses that more closely mirror clinical behaviour. Transcriptomic profiling further revealed robust activation of MYC target programs and mTORC1 signalling, accompanied by elevated oxidative phosphorylation and glycolytic activity, indicative of the highly proliferative and metabolically active state exhibited by AML cells in vivo. These findings demonstrate that our patient-specific, 3D bioprinted system provides a high-fidelity model. This model faithfully recapitulates AML physiology and metabolic features while capturing inter-patient variability. Consequently, it offers a more reliable and predictive platform for preclinical drug assessment.
Soluble Epoxide Hydrolase Inhibition Regulates Septoclast Activity to Promote Long Bone Growth and Fracture Healing by Enhancing Endothelial-to-Mesenchymal Notch Signalling.
Chen W, Liu L, Wang X … +8 more , Li J, Zhang J, Shi X, Sun Q, Chang X, Zhang J, Zhao J, Wang F
Cell Prolif · 2026 Jun · PMID 42297360 · Publisher ↗
Endochondral ossification is essential for the development of appendicular bones, physiological bone remodelling and fracture healing. Recent studies have identified mesenchymal stromal cell-derived FABP5 septoclasts (SC...
Endochondral ossification is essential for the development of appendicular bones, physiological bone remodelling and fracture healing. Recent studies have identified mesenchymal stromal cell-derived FABP5 septoclasts (SCs) as key mediators for the growth and repair of long bones, particularly in cartilage matrix degradation and growth plate remodelling via the secretion of matrix metalloproteinases. Our previous study has shown that soluble epoxide hydrolase (sEH) inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), promotes long bone growth and bone repair by enhancing H-type vessel-coupled osteogenesis. However, whether TPPU treatment regulates SC activity, thereby promoting long-bone growth and fracture healing, remains unclear. Here, our in vitro and in vivo results showed that TPPU treatment promoted long-bone growth in newborn mice and regulated the hypertrophic layer in the growth plate, with a reduced ratio of hypertrophic cartilage (HC) to proliferative cartilage (PC) width. Furthermore, TPPU treatment enhanced SC activity, as evidenced by elevated expression of MMP9 and FABP5 in the metaphysis near the growth plate. Simultaneously, TPPU induced FABP5 SC-like cells to degrade chondrocytes in co-cultured human umbilical vein endothelial cells (HUVECs) and human dental pulp stem cells (hDPSCs). Mechanistically, TPPU enhanced the crosstalk of co-cultured HUVECs and hDPSCs to activate the NOTCH signalling pathway in hDPSCs by upregulating HIF-1α expression in HUVECs. Furthermore, TPPU enhanced fracture healing by inducing more FABP5 SCs and MMP9 secretion at the fracture site. Collectively, these findings highlight sEH as a promising therapeutic target that regulates endochondral ossification through inducing SC activity, offering new opportunities for bone development and repair.
Small Extracellular Vesicle-Associated Polymeric Immunoglobulin Receptor in Primary Liver Cancer: From Immunological Mediator to Oncogenic Driver and Biomarker.
Hsu JTR, Wong SWK, Ping JYW
Cell Prolif · 2026 Jun · PMID 42285611 · Publisher ↗
Abstract loading — click title to view on PubMed.
Dental Pulp Stem Cell-Derived Intracellular Vesicles Inhibit OSCC by Delivering PTEN to Suppress PI3K/AKT/mTOR Signalling Pathway.
Luo Y, Qin Q, She W … +8 more , Wang X, Li X, Shu C, Li R, Li Z, Fu D, He Y, Ye Q
Cell Prolif · 2026 Jun · PMID 42272134 · Publisher ↗
Oral squamous cell carcinoma (OSCC) represents a globally predominant type of oral malignancy with escalating incidence, featuring aggressive biological behaviour, prominent metastatic potential and poor clinical outcome...
Oral squamous cell carcinoma (OSCC) represents a globally predominant type of oral malignancy with escalating incidence, featuring aggressive biological behaviour, prominent metastatic potential and poor clinical outcomes. Emerging evidence positions dental pulp stem cell-sourced intracellular vesicles (DPSC-IVs) as novel therapeutic vectors in regenerative oncology, citing their low immunogenicity, favourable safety profile and ability to modulate tumour microenvironment. In this study, DPSC-IVs significantly inhibited OSCC progression both in vitro and in vivo, suppressing tumour cell proliferation, invasion and colony formation while simultaneously promoting apoptosis. Notably, the antitumor effect of DPSC-IVs was further enhanced by combining them with autophagy inhibitor 3-methyladenine (3-MA), which synergistically suppressed the PI3K/AKT/mTOR pathway and enhanced mitochondrial stress while suppressing residual cytoprotective autophagy. Mechanistically, DPSC-IVs served as carriers of PTEN into OSCC cells, which in turn suppressed oncogenic PI3K/AKT signalling and induced excessive mitophagy. Taken together, this study indicated that DPSC-IVs could suppress OSCC through dual mechanisms, highlighting their potential as a promising and clinically translatable therapeutic option with advantages in safety and scalable production.
Targeting PCSK9 in Vascular Smooth Muscle Cells: An Effective Strategy to Suppress Ferroptosis and Attenuate Abdominal Aortic Aneurysm Progression.
Xia M, Li M, Chen Y … +11 more , Chen J, Cui Y, Zheng XL, Yang J, Li B, Ma X, Liu M, Fan G, Peng J, Dai X, Tang Z
Cell Prolif · 2026 Jun · PMID 42269711 · Publisher ↗
Abdominal aortic aneurysm (AAA) lacks effective pharmacotherapy. This study examines whether proprotein convertase subtilisin/kexin type 9 (PCSK9) drives ferroptosis in vascular smooth muscle cells (VSMCs) and whether it...
Abdominal aortic aneurysm (AAA) lacks effective pharmacotherapy. This study examines whether proprotein convertase subtilisin/kexin type 9 (PCSK9) drives ferroptosis in vascular smooth muscle cells (VSMCs) and whether its pharmacological degradation mitigates disease progression. PCSK9 is enriched in VSMCs of human AAA and in murine models induced by PPE or Ang II. SMC-specific PCSK9 overexpression (PCSK9) increases aortic diameter, aggravates elastin fragmentation and collagen deposition and elevates MMP2/9 expression. Within aortic lesions, PCSK9 enhances iron accumulation and lipid peroxidation while reducing glutathione GPX4, consistent with ferroptosis. In primary VSMCs, PCSK9 overexpression suppresses GPX4 and glutathione, increases malondialdehyde and Fe levels and impairs viability, whereas PCSK9 knockdown attenuates Ang II-induced ferroptosis. Mechanistically, PCSK9 triggers ferritinophagy, as shown by decreased ferritin heavy chain-1 (FTH1) and nuclear receptor coactivator-4 (NCOA4), an increased LC3-II/I ratio and enhanced FTH1-LAMP1 colocalisation. Autophagy inhibition with bafilomycin A1 blocks Fe accumulation and rescues ferroptotic indices. The cell-permeable peptide Cadd4 promotes PCSK9 degradation, restores FTH1 and NCOA4 and suppresses ferroptosis in VSMCs. In PPE and Ang II models, Cadd4 reduces aortic dilation, preserves medial structure and normalises ferroptosis and ferritinophagy markers. PCSK9 drives ferritinophagy-dependent ferroptosis in VSMCs, and Cadd4 represents a promising therapeutic strategy for AAA.
EXPRESSION OF CONCERN: Photodynamic Therapy with 5-Aminolaevulinic Acid and DNA Damage: Unravelling Roles of p53 and ABCG2.
Cell Prolif · 2026 Jun · PMID 42244218 · Publisher ↗
Abstract loading — click title to view on PubMed.
High Uric Acid Promotes Stem Leydig Cell Senescence by CCDC90B Mediates Mitochondrial Quality Control Imbalance.
Huang J, Wang A, Li X … +6 more , Huang P, Zeng K, Sun L, Li M, Chen Y, Wang J
Cell Prolif · 2026 Jun · PMID 42242294 · Publisher ↗
Hyperuricemia is a common metabolic disease and an important risk factor for low testosterone levels in men. The functional homeostasis of stem Leydig cells (SLCs) is crucial for maintaining testosterone levels. However,...
Hyperuricemia is a common metabolic disease and an important risk factor for low testosterone levels in men. The functional homeostasis of stem Leydig cells (SLCs) is crucial for maintaining testosterone levels. However, the potential molecular mechanism of how high uric acid (UA) levels affect SLC function remains to be elucidated. Here, we reveal that at the single-cell RNA sequencing level, SLCs exhibit senescence under high UA conditions. Mechanistically, UA binds to CCDC90B, leading to its significant accumulation within cells. This exacerbates the influx of calcium ions into mitochondria, resulting in mitochondrial quality control (MQC) imbalance. In addition, at the level of organoids and transgenic mice, we observe SLC senescence is alleviated and considerable testosterone recovery after AAV8-CCDC90B treatment. In summary, these results indicate that SLC senescence under high UA is regulated in a MQC-dependent manner, with CCDC90B being a key regulatory target. Meanwhile, AAV-mediated gene therapy may offer a promising therapeutic approach for patients with low testosterone levels.
YTHDF3 Enhances Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in Osteoporosis by Promoting TBX19 Expression.
Tao Q, Ye Q, Yang C … +7 more , Xie Y, Long X, Bai L, Zhang Z, Li Q, Tan D, Xiao J
Cell Prolif · 2026 Jun · PMID 42235938 · Publisher ↗
N-methyladenosine (mA) modification is critically involved in regulating the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), yet the functional contributions of mA reader proteins in osteoporosi...
N-methyladenosine (mA) modification is critically involved in regulating the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), yet the functional contributions of mA reader proteins in osteoporosis remain poorly defined. In this study, we found that osteoporosis in rats correlates with severe bone loss and diminished osteogenic potential of BMSCs, accompanied by down-regulation of the mA reader YTHDF3. Functional assays showed that YTHDF3 promotes osteogenic differentiation of BMSCs. RNA-sequencing analysis identified the transcription factor TBX19 as a key downstream mediator of YTHDF3. Subsequent investigations confirmed that Tbx19 knockdown not only attenuated the osteogenic capacity of BMSCs but also abrogated the pro-osteogenic effect of Ythdf3 overexpression. Moreover, in vivo experiments demonstrated that Ythdf3 overexpression enhances the bone-forming ability of osteoporotic BMSCs. Collectively, our results reveal that YTHDF3 acts as a positive regulator of BMSC osteogenesis, largely through regulating TBX19, and that its down-regulation contributes to osteoporotic pathogenesis. These findings propose YTHDF3 as a novel potential therapeutic target for the treatment of osteoporosis.
Suppression of Retinal Neovascularisation by Tetrahedral Framework Nucleic Acids-Resveratrol Via Dual Anti-Angiogenesis and Anti-Inflammation.
Jin Y, Cai T, Huang J … +5 more , Chen L, Lin Y, Liu J, Wang Y, Ding X
Cell Prolif · 2026 Jun · PMID 42233589 · Publisher ↗
Retinal neovascular diseases, such as retinopathy of prematurity and diabetic retinopathy, threaten vision by disrupting retinal structure and function through pathological neovascularisation and chronic inflammation. Ex...
Retinal neovascular diseases, such as retinopathy of prematurity and diabetic retinopathy, threaten vision by disrupting retinal structure and function through pathological neovascularisation and chronic inflammation. Existing anti-VEGF therapies primarily target angiogenesis, offering limited control over inflammation and requiring repeated administration. Here, we developed a resveratrol (RSV)-loaded tetrahedral framework nucleic acid nanostructure (tFNAs-RSV) to achieve concurrent anti-angiogenic and anti-inflammatory effects. tFNAs provided a biocompatible, stable and penetration-efficient carrier that enhanced RSV ocular delivery and bioactivity. In hypoxia-induced retinal neovascularisation models, tFNAs-RSV markedly reduced neovascular lesion area, vascular leakage and retinal inflammatory cell infiltration. Mechanistically, tFNAs-RSV suppressed HIF-1 signalling and inhibited the p38 MAPK pathway and NF-κB p65 pathway. Collectively, these results validate tFNAs-RSV as a promising nanoplatform for treating retinal neovascular diseases, with an emphasis on inhibiting neovascularisation and inflammation.
A Specific tRNA Half, 3'tiRNA-GlyGCC, Regulates Hypoxic Pulmonary Artery Smooth Muscle Cell Proliferation via Myrf-Mediated Endoplasmic Reticulum Stress.
Zhang L, Guan X, Zhu X … +9 more , Hao Y, Xu Y, Yuan H, Gao D, Du H, Li J, Cao W, Ma C, Wang X
Cell Prolif · 2026 May · PMID 42215285 · Publisher ↗
Pulmonary artery smooth muscle cell (PASMC) proliferation is a hallmark of the pathogenesis of hypoxic pulmonary hypertension (PH), and endoplasmic reticulum stress (ERS) plays a crucial role. Many studies have implicate...
Pulmonary artery smooth muscle cell (PASMC) proliferation is a hallmark of the pathogenesis of hypoxic pulmonary hypertension (PH), and endoplasmic reticulum stress (ERS) plays a crucial role. Many studies have implicated that tRNA-derived fragment, tiRNAs, in a variety of biological processes, but their roles in hypoxia-induced PASMC ERS and proliferation have not been investigated. In this study, we identified a significantly upregulated 3'tiRNA-GlyGCC in hypoxic mouse lung tissues using Arraystar small RNA microarray analysis. Functional assays, including CCK8, EdU incorporation, Western blot, and immunofluorescence, demonstrated that inhibition of 3'tiRNA-GlyGCC reversed hypoxia-induced ERS and proliferation in PASMCs. Mechanistically, 3'tiRNA-GlyGCC interacts with the eukaryotic translation elongation factor 1 alpha 1 (Eef1a1) protein and reduces the binding capacity between Eef1a1 and myelin regulatory factor (Myrf) mRNA, leading to decreased stability of Myrf mRNA. Additionally, 3'tiRNA-GlyGCC targets Myrf mRNA and inhibits its expression. We further verified that angiogenin (Ang) mediated the biogenesis of 3'tiRNA-GlyGCC under hypoxic conditions. Collectively, these findings highlight a novel mechanism underlying PASMC ERS and proliferation and suggest that 3'tiRNA-GlyGCC could serve as a potential therapeutic target for hypoxic PH.
Co-Culture of Mammalian Cells and Photosynthetic Microorganisms for Oxygen Supply in Engineered Tissues.
Wang M, Hala AF, van der Niet V … +8 more , Bok ST, Özenler AK, Janssen M, Barbosa MJ, Martens D, Wijffels RH, Malda J, de Ruijter M
Cell Prolif · 2026 May · PMID 42191666 · Publisher ↗
Ensuring an adequate supply of oxygen remains a significant challenge in the development of large engineered tissue constructs in the field of tissue engineering. To address this, novel strategies have recently been intr...
Ensuring an adequate supply of oxygen remains a significant challenge in the development of large engineered tissue constructs in the field of tissue engineering. To address this, novel strategies have recently been introduced, including the incorporation of photosynthetic microorganisms into engineered tissues. However, to take the full advantage of this co-culture approach, careful selection of photosynthetic microorganisms and a better understanding of their long-term interactions with mammalian cells are required. Here, we first examined the effects of continuous 28-day light exposure on the proliferation and biofunctionality of mammalian cells. We observed that articular cartilage-derived chondroprogenitor cells (ACPCs) did better withstand light exposure under chondrogenic conditions than mesenchymal stromal cells (MSCs). Next, four different photosynthetic microorganisms, capable of growing at 37°C, were co-cultured with cartilage cells. Among them, Leptolyngbya sp. (Leptolyngbya) and Synechococcus sp. (Synechococcus) did not compromise the morphology and chondrogenic capacity of mammalian cells in vitro over 28 days, whereas Chlorella sorokiniana (Chlorella) inhibited chondrogenesis. This inhibition might due to excessive oxygen release by Chlorella in chondrogenic culture medium, as Leptolyngbya and Synechococcus did not produce detectable oxygen under the same culture conditions. To further explore their potential for oxygen delivery to other tissue-derived cells, we also assessed the growth rate and oxygen production of these four microorganisms in different mammalian cell culture media. We found that the composition, especially the presence of trace elements in tissue medium, critically influenced oxygen production. The tested microorganisms were able to grow and release oxygen in different mammalian cell culture media typically used for the propagation of cardiac, cartilage and liver cells, highlighting their flexible metabolic pathways across the different environments. This study emphasizes the importance of carefully selecting photosynthetic microorganisms for different tissue types, ensuring a balance between oxygen production and the specific nutritional demands of mammalian cells.
Zeb2 Controls Retinal Physiological and Pathological Angiogenesis by Regulating Astrocyte Proliferation and Differentiation.
Liu J, Guo Y, Xiang K … +3 more , Wang S, Xiao D, Xiang M
Cell Prolif · 2026 May · PMID 42186920 · Publisher ↗
Retinal angiogenesis relies on a precisely timed interaction between astrocytes and endothelial cells (ECs), yet the transcriptional regulatory program underlying this complex neurovascular crosstalk remains poorly chara...
Retinal angiogenesis relies on a precisely timed interaction between astrocytes and endothelial cells (ECs), yet the transcriptional regulatory program underlying this complex neurovascular crosstalk remains poorly characterized. Here, we define Zeb2 as a pivotal transcriptional modulator of retinal astrocyte function that coordinates developmental and pathological vascular growth. It is transiently expressed in retinal astrocyte progenitor cells during development and re-induced under pathological hypoxia. Conditional ablation of Zeb2 in retinal astrocytes enhanced their proliferation, migration, and maturation by upregulating VEGFA and altering other signalling, leading to excessive superficial vascular growth during development. In oxygen-induced retinopathy, Zeb2 inactivation exacerbated pathological neovascularization while impairing reparative revascularization, which is associated with a transcriptional signature favouring tuft ECs over tip ECs. Mechanistically, it inhibited the neurotoxic A1 astrocyte identity, resulting in dampened inflammatory response and diminished genetic program promoting revascularization and/or preventing neovascularization including Plxnd1, Nrf2, and FGF2 signalling. These findings establish Zeb2 as an oxygen-sensitive regulator of astrocyte function that differentially modulates physiological and pathological angiogenesis, highlighting its potential as a therapeutic target in proliferative retinopathies.
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