Cell. Mol. Biol. Lett. [JOURNAL]
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200 papers
Runx2 downregulates Lpl expression through super-silencer formation to alter lipid metabolism in Zhu Schwann cells after nerve injury.
Zhu Z, Kuang R, Su S … +9 more , Zhang Y, Wu G, Zhang Y, Pang V, Zhou X, Yang Y, Li G, He B, Xu Y
Cell Mol Biol Lett · 2025 Oct · PMID 41107728 · Full text
BACKGROUND: Phenotypic transformation of Schwann cells (SCs) plays a crucial role in nerve regeneration. Previous studies have demonstrated that Runx2 significantly influences the biological behavior of SCs. Nonetheless,...
BACKGROUND: Phenotypic transformation of Schwann cells (SCs) plays a crucial role in nerve regeneration. Previous studies have demonstrated that Runx2 significantly influences the biological behavior of SCs. Nonetheless, the regulatory mechanisms that govern its epigenetic regulation are not yet fully elucidated. METHODS: To facilitate this investigation, an adenovirus for the overexpression of Runx2 was constructed. Healthy adult Sprague-Dawley rats, weighing between 100 and 150 g and irrespective of sex, were randomly selected for the study. After establishing a model of sciatic nerve crush injury, tissue samples were harvested for histological analysis at both 4 and 7 days post-injury. In vitro, an Runx2-overexpressing SC line was established. Thorough analysis of transcriptome data, coupled with CUT&Tag sequencing of histones and transcription factors in SCs following Runx2 overexpression, was conducted. Additionally, single-cell RNA sequencing data from GSE216665 were incorporated to elucidate the mechanistic role of Runx2. The findings were subsequently validated through dual-luciferase assays. RESULTS: Following nerve crush injury, Runx2-positive SCs were identified at the injury site. Through comprehensive multiomics analysis, we discovered that lipid metabolism was disrupted in Runx2-overexpressing SCs. Further investigation established a detailed super-silencer landscape in these cells, revealing that elevated Runx2 levels form a super-silencer within the transcriptional regulatory region of the Lpl gene, thereby downregulating Lpl expression. CONCLUSIONS: Runx2 can modulate the biological behavior of SCs by forming super-silencers that interfere with the expression of lipid metabolism genes, such as Lpl, thereby altering the metabolic capacity of SCs.
YAP contributes to liver injury through mediating capillarization of liver sinusoidal endothelial cells via GATA6/eNOS signaling.
Wang J, Shen Z, Chen G … +13 more , Dai W, Mei Z, Shen B, Guo Y, Wang J, Zhangdi H, Zhang Q, Gao J, Ge Q, Zhou H, Dong H, Lu L, Cai X
Cell Mol Biol Lett · 2025 Oct · PMID 41094388 · Full text
BACKGROUND: Capillarization of liver sinusoidal endothelial cells (LSECs) is a central event in response to liver injury. In this study, we investigated the role of Yes-associated protein 1 (YAP1, also known YAP) in LSEC...
BACKGROUND: Capillarization of liver sinusoidal endothelial cells (LSECs) is a central event in response to liver injury. In this study, we investigated the role of Yes-associated protein 1 (YAP1, also known YAP) in LSEC capillarization and liver injury. METHODS: YAP expression was assessed in liver samples from mice injured by CCl injection and DDC diet. EC-specific Yap1 conditional knockout mice (Yap1) were generated by breeding Yap1 mice with Cdh5-Cre mice. HA-PEI/siYap1 nanoparticles were applied to specifically inhibit YAP expression in LSECs. RESULTS: YAP was primarily expressed in LSECs, and its expression was elevated during liver fibrosis. EC-specific Yap1 deficiency significantly increased the fenestrae in LSECs and mitigated hepatocyte death and liver fibrosis. Overexpression of YAP in EC aggravated capillarization, hepatocyte death, and liver fibrosis. Mechanistically, YAP inhibited Gata6 transcription via binding to its promoter and thus resulted in LSEC capillarization. Overexpression of GATA6 in EC alleviated capillarization and liver fibrosis by activating Nos3 transcription. Moreover, specific delivery of HA-PEI-siYap1 nanoparticles to LSEC alleviated liver injury in mice. CONCLUSIONS: YAP-GATA6/eNOS signaling is essential in LSEC capillarization and subsequent hepatocyte death. Interventions targeting YAP in LSECs offer a promising strategy for the treatment of liver fibrosis.
AXL activation governs the liver microenvironment to protect ischemia-reperfusion injury by suppressing NLRP3 inflammasome.
Liu D, Zhan M, Yao L … +11 more , Liu X, Zhang R, Zha L, Zhang X, Xu Y, Fang Q, Cai H, Yan Q, Wang W, Du J, Chen L
Cell Mol Biol Lett · 2025 Oct · PMID 41087895 · Full text
BACKGROUND: Ischemia-reperfusion (I/R) injury frequently arises during liver surgery and significantly contributes to postoperative liver failure and graft dysfunction. Macrophage-mediated pyroptosis cascade plays a cruc...
BACKGROUND: Ischemia-reperfusion (I/R) injury frequently arises during liver surgery and significantly contributes to postoperative liver failure and graft dysfunction. Macrophage-mediated pyroptosis cascade plays a crucial effect in liver I/R injury. The attribution of pyroptosis in macrophage reprogramming and hepatic microenvironment during liver I/R remain unclear. Here, we identify AXL as a hepatic macrophage-enriched gene that regulates pyroptosis in I/R injury. METHODS: We collected liver grafts to test the relationship between phosphorylated AXL (p-AXL) and degree of hepatic injury. We isolated primary mouse hepatocytes and macrophages for hypoxia/reoxygenation (H/R) treatment and coculture, and used macrophage depletion mice to reveal the unique function of AXL in hepatic macrophages. Mice were treated with activators and inhibitors of AXL, NLRP3, and XBP1, and subjected to liver I/R to determine the mechanism underlying AXL-mediated modulation of the hepatic microenvironment. RESULTS: We found that AXL inhibition and NLRP3-induced pyroptosis was strongly associated with the degree of liver I/R injury. Further analysis revealed that AXL activation in macrophages suppressed hepatic I/R-induced pyroptosis. AXL activation with Gas6, a high-affinity ligand for AXL, significantly attenuated liver I/R injury and improved the hepatic microenvironment. Mechanistically, AXL activation impeded the IRE1-XBP1s axis to suppress NLRP3 inflammasome activation, which promoted hepatic macrophages to an alternative-like polarization, thereby enhancing the hepatic immune environment to attenuate liver I/R injury. CONCLUSIONS: This study not only elucidates how AXL reprograms macrophages but also suggests a therapeutic target for mitigating liver I/R injury.
Inhibition of DHHC9-mediated CD36 palmitoylation lessens high-fat diet (HFD)-induced impairment of pubertal mammary gland development through the JNK-ERK pathway.
Fu Y, Zhang F, Lang L … +16 more , Liang S, Wang J, Zhang S, Deng K, Liu J, Cai L, Zhang Y, Yan L, Ren G, Kang H, Wang L, Zhu C, Wu R, Shu G, Jiang Q, Wang S
Cell Mol Biol Lett · 2025 Oct · PMID 41087856 · Full text
BACKGROUND: CD36, a vital fatty acid translocase, has been reported to participate in multiple physiological functions through palmitoylation mediated by zinc finger Asp-His-His-Cys-type palmitoyltransferases (DHHCs). Th...
BACKGROUND: CD36, a vital fatty acid translocase, has been reported to participate in multiple physiological functions through palmitoylation mediated by zinc finger Asp-His-His-Cys-type palmitoyltransferases (DHHCs). This study aimed to investigate the possible involvement of DHHC-mediated CD36 palmitoylation in high-fat diet (HFD)-induced impairment of pubertal mammary gland development and explore the underlying mechanisms involved. METHODS: Palmitic acid (PA)-treated HC11 cells were used as the in vitro high-fat model, and the cell proliferation was examined by 5-Ethynyl-2'-deoxyuridine (EdU) incorporation assay. The palmitoylation of CD36 was determined by the acyl-biotin exchange (ABE) method. The expression of CD36, proliferative genes, and signaling molecules was detected by immunoblotting. The cellular localization of CD36 was determined by immunofluorescence. The bindings of CD36 with zinc finger DHHC-type palmitoyltransferases 9 (DHHC9) or Fyn/Lyn were detected by co-immunoprecipitation (Co-IP). The palmitoylation inhibitor 2-bromopalmitate (2BP), DHHC9 knockdown, and point mutation of CD36 cysteine residues were applied to construct a CD36 palmitoylation deficiency model in vitro to investigate the effects of CD36 palmitoylation on HC11 proliferation. In vivo, the pubertal mice were treated with HFD and/or 2BP. Mammary gland morphology was determined by whole mount staining, and the underlying mechanisms were verified by the methods used in the in vitro system. RESULTS: In vitro, the palmitoylation inhibitor 2BP eliminated PA-inhibited HC11 proliferation and inhibited CD36 palmitoylation and localization on the plasma membrane. Meanwhile, the binding of DHHC9 and CD36 in PA-treated HC11 cells was repressed by 2BP. In addition, both knockdown of DHHC9 and point mutation of CD36 cysteine residues suppressed the membrane palmitoylation and localization of CD36 and stimulated the proliferation of PA-treated HC11 cells. Furthermore, in PA-treated HC11 cells, the inhibition of CD36 palmitoylation, the knockdown of DHHC9, and the mutation of CD36 cysteine residues resulted in decreased formation of the CD36/Fyn/Lyn complex. Correspondingly, the downstream c-jun n-terminal kinase 1 (JNK1) pathway was inhibited, and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway was activated. Moreover, inhibition of the JNK pathway with SP600125 promoted the proliferation of PA-treated HC11 cells via activation of the ERK1/2 pathway. In vivo, the palmitoylation inhibitor 2BP ameliorated HFD-induced impairment of mammary gland development in pubertal female mice, which was associated with a decrease in DHHC9-mediated CD36 palmitoylation in the plasma membrane, a reduction in the CD36/Fyn/Lyn complex, inhibition of the JNK1 pathway, and activation of the ERK1/2 pathway. CONCLUSIONS: This study revealed that inhibition of DHHC9-mediated CD36 palmitoylation mitigated HFD-induced impairment of pubertal mammary gland development via the JNK1-ERK1/2 pathway.
Epitranscriptomic modifications in programmed cell death: mechanistic insights and implications for liver diseases.
Chen L, Lu Y, Deng A … +9 more , Cao J, Jin F, Huang H, Pan F, Liu Y, Li Y, Tong X, Yao H, Du J
Cell Mol Biol Lett · 2025 Oct · PMID 41062946 · Full text
Epitranscriptomic modifications, as a dynamic and reversible system of chemical modifications, have emerged as a key regulatory hub for programmed cell death (PCD) by finely modulating the RNA metabolic network. During t...
Epitranscriptomic modifications, as a dynamic and reversible system of chemical modifications, have emerged as a key regulatory hub for programmed cell death (PCD) by finely modulating the RNA metabolic network. During the pathological progression of liver diseases, aberrant alterations in epitranscriptomic modifications can disrupt the dynamic equilibrium of PCD signaling pathways, leading to excessive cell death or abnormal survival of hepatocytes, thereby driving the development of metabolic dysfunction-associated steatotic liver disease (MASLD), viral hepatitis, alcohol-associated liver disease (ALD), hepatic fibrosis, and hepatocellular carcinoma (HCC). A thorough investigation into the molecular mechanisms of epitranscriptomic modifications in PCD pathways and their roles in liver diseases not only aids in elucidating the pathogenesis of liver disorders but also holds the potential to provide new biomarkers and therapeutic targets for the diagnosis, prognosis, and treatment of liver diseases. This review systematically summarizes the molecular mechanisms of epitranscriptomic modifications, delves into the complex regulatory networks between epitranscriptomic modifications and PCD, elaborates on their roles in liver diseases, and provides a comprehensive overview of current drugs targeting epitranscriptomic modifications. These insights offer new treatment ideas for liver diseases and new directions for precision medicine research.
LncRNA-like MMP14 RNA facilitates colorectal cancer metastasis by suppressing H3K27cr at the STARD13 promoter region.
Li M, Gao Y, Sun X … +11 more , Zheng W, Zhang M, Wang C, Chu W, Yang X, Wang L, Zheng M, Xue W, Dong F, Pei D, Liao M
Cell Mol Biol Lett · 2025 Oct · PMID 41053540 · Full text
BACKGROUND: MMP14 protein has been recognized to promote tumor metastasis through protease activity, yet drugs targeting the protein fail to improve survival rates, suggesting the presence of non-protein regulatory mecha...
BACKGROUND: MMP14 protein has been recognized to promote tumor metastasis through protease activity, yet drugs targeting the protein fail to improve survival rates, suggesting the presence of non-protein regulatory mechanisms. This study aims to explore the roles and mechanisms by which MMP14 RNA facilitates colorectal cancer (CRC) metastasis. METHODS: Transwell assays and animal experiments utilizing loss-of-function and gain-of-function approaches were employed to assess the roles of MMP14 RNA in facilitating CRC metastasis. A combination of immunoprecipitation assays, scRNA-seq analysis, and western blotting was conducted to elucidate the underlying mechanisms by which MMP14 RNA promoted CRC metastasis. RESULTS: Our study revealed that MMP14 RNA was highly expressed in CRC tissues and correlated with poor prognosis. The overexpression of MMP14 RNA facilitated metastasis both in vitro and in vivo. Mechanistically, MMP14 RNA interacted with the distal promoter of STARD13 and bound to the N-terminal of SIRT3, facilitating its recruitment to the promoter region. This cascade of events reduced H3K27cr levels at the STARD13 promoter, thereby inhibiting STARD13 transcription and ultimately promoting CRC metastasis. Furthermore, we proved that silencing MMP14 RNA had a more significant inhibitory effect on tumor metastasis compared with inhibiting the MMP14 protein. CONCLUSIONS: The study elucidated an lncRNA-like mechanism by which MMP14 RNA facilitated CRC metastasis via RNA-directed chromatin remodeling.
Endogenous cardiac catecholaminergic systems in cardiac development, physiology, and pathophysiology.
Zheng Y, Ren RY, Wu X … +7 more , Qu F, Grassam-Rowe A, Sun T, Ou X, Tan X, Huang M, Lei M
Cell Mol Biol Lett · 2025 Oct · PMID 41046318 · Full text
Catecholamines, canonically associated with the sympathetic nerves and the adrenal medulla, are also produced by neuroparacrine cells within the heart. Despite their putative importance, the precise functions of these ne...
Catecholamines, canonically associated with the sympathetic nerves and the adrenal medulla, are also produced by neuroparacrine cells within the heart. Despite their putative importance, the precise functions of these neuroparacrine cells in the heart are not well understood and their clinical implications remain to be defined. In this review, we first explore the historical context and recent advances in research on intrinsic cardiac adrenergic (ICA) cells, focusing on their unique characteristics, distributions, and progenitor-like potential during cardiac development. We then examine their contributions to both physiological and pathological cardiac states. We further discuss a recently identified population of catecholaminergic cardiomyocytes; we discuss their involvement in cardiac development, maturation, and their potential interaction with sympathetic innervation during development. By reviewing these findings, we provide new insights into the endogenous production of catecholamines within the heart and its relevance to cardiac development, physiology and disease, and its potential clinical implications.
Bridging pancreatic and hepatic development: overlapping genes and their role in diabetes.
Ghanem SS, Al-Barazenji T, Badi R … +1 more , Abdelalim EM
Cell Mol Biol Lett · 2025 Oct · PMID 41044495 · Full text
Diabetes mellitus is a complex metabolic disorder characterized by hyperglycemia due to impaired insulin production, action, or both. The Pancreas and Liver play central roles in glucose regulation, and their dysfunction...
Diabetes mellitus is a complex metabolic disorder characterized by hyperglycemia due to impaired insulin production, action, or both. The Pancreas and Liver play central roles in glucose regulation, and their dysfunction is critical to the onset and progression of specific types of diabetes, including type 2 diabetes and certain forms of monogenic diabetes. While these organs have distinct physiological roles, they originate from the foregut endoderm and share key developmental regulators and signaling pathways. This review explores the overlapping transcription factors and genes that are essential for both pancreatic and hepatic development and function. These dual-role genes not only govern early organogenesis but are also implicated in diabetes pathogenesis, underscoring their significance in metabolic homeostasis. We highlight how interorgan signaling, particularly between hepatokines and pancreatic islet cells, contributes to the maintenance or disruption of glucose metabolism. Furthermore, we discuss the clinical implications of these shared pathways, emphasizing how insights from developmental biology can inform precision diagnostics and therapeutic strategies for diabetes. Finally, we consider how emerging tools, such as pluripotent stem cell-based disease models and gene editing and multi-omics approaches, are transforming our understanding of gene function and disease progression. By bridging the developmental and metabolic landscapes of the pancreas and liver, this review provides a comprehensive framework for uncovering novel regulators of diabetes and paves the way toward targeted, personalized treatment strategies.
RSL3 promotes PARP1 apoptotic functions by distinct mechanisms during ferroptosis.
Chen D, Xie F, Mo Y … +3 more , Qin D, Zheng B, Chen L
Cell Mol Biol Lett · 2025 Oct · PMID 41039223 · Full text
BACKGROUND: The classical ferroptosis activator RSL3 targets enzymes with nucleophilic active sites, primarily acting on glutathione peroxidase 4 (GPX4) to trigger ferroptosis. Recent studies identify RSL3 as a potential...
BACKGROUND: The classical ferroptosis activator RSL3 targets enzymes with nucleophilic active sites, primarily acting on glutathione peroxidase 4 (GPX4) to trigger ferroptosis. Recent studies identify RSL3 as a potential pro-apoptotic agent. However, the mechanism by which RSL3 induces apoptosis during ferroptosis remains elusive. Poly(ADP-ribose) polymerase (PARP1) determines cell fate in response to DNA damage, where its loss or cleavage by activated caspase-3 induces apoptosis to attenuate tumor progression. We elucidate a novel mechanism underlying PARP1 regulation, encompassing both its caspase-dependent cleavage and full-length depletion during RSL3-mediated ferroptosis-apoptosis crosstalk. METHODS: To investigate the role of RSL3 during ferroptosis, we treated several cancer cells of different histological types with varying doses of RSL3 to induce apoptosis. The regulatory proteins of PARP1 were analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. The N-methyladenosine (mA) modification level of PARP1 was determined by mA RNA immunoprecipitation (MeRIP)-qPCR analysis. Additionally, an RNA immunoprecipitation (RIP)-qPCR assay was performed to identify the target protein of the mA site of PARP1. Furthermore, we established a mouse xenograft model of PARP inhibitor (PARPi)-resistant cells to analyze the effect of RSL3 on PARPi-resistant tumor growth. RESULTS: RSL3 triggers two parallel apoptotic pathways via increasing reactive oxygen species (ROS) production during ferroptosis: (1) caspase-dependent PARP1 cleavage and (2) DNA damage-dependent apoptosis resulting from reduced full-length PARP1. The latter occurs through inhibition of METTL3-mediated mA modification and subsequent suppression of PARP1 translation. Moreover, we found that RSL3 retains pro-apoptotic functions in PARPi-resistant cells and effectively inhibits PARPi-resistant xenograft tumor growth in vivo. CONCLUSIONS: RSL3 orchestrates ferroptosis-apoptosis crosstalk via PARP1, demonstrating therapeutic potential against tumorigenesis, particularly in PARPi-resistant malignancies.
The emerging role of human transmembrane RGD-based counter-receptors of integrins in health and disease.
Cabañas C, Rossi E, Bartolomé RA … +4 more , Doberstein K, Altevogt P, Casal JI, Bernabeu C
Cell Mol Biol Lett · 2025 Oct · PMID 41039222 · Full text
Most of the canonical Arg-Gly-Asp (RGD)-containing integrin ligands are extracellular matrix proteins, such as fibronectin, vitronectin and fibrinogen, which regulate cell-ECM adhesion processes. However, during the last...
Most of the canonical Arg-Gly-Asp (RGD)-containing integrin ligands are extracellular matrix proteins, such as fibronectin, vitronectin and fibrinogen, which regulate cell-ECM adhesion processes. However, during the last years, several reports have demonstrated the existence of non-canonical RGD-containing integrin ligands that are cell surface transmembrane proteins. At variance with the canonical extracellular matrix integrin ligands, the RGD-containing cell surface integrin ligands are involved in cell-cell adhesion processes and function as "integrin counter-receptors". We propose in this review grouping these transmembrane proteins, which include endoglin, cadherin-5, cadherin-6, cadherin-17, ADAM15, and L1CAM, under the newly coined acronym RGD-ICRs (RGD-containing Integrin Counter-Receptors). We present and discuss the structure of RGD-ICRs, their RGD-based interactions with integrins, the specific signaling pathways triggered in different cell types, as well as their pathophysiological involvement. It can be postulated that RGD-ICRs constitute an emerging group of non-canonical RGD-based integrin counter-receptors. In spite of being encoded by different and independent genes and involved in different pathophysiological processes, all of them appear to have undergone a strong evolutionary convergence in order to acquire the same functional capacity to bind integrins via the RGD motif. Importantly, these RGD-ICRs are also emerging as novel biomarkers and therapeutic targets, with promising clinical potential in a wide array of pathologies.
Crosstalk between endothelial cells and osteoblasts stimulates ALP via Notch signaling and RANKL/OPG ratio independently of Notch signaling in vitro.
Wirsig K, Bürger N, Bernhardt A
Cell Mol Biol Lett · 2025 Oct · PMID 41039204 · Full text
BACKGROUND: Bone remodeling requires a complex interplay between osteogenesis and angiogenesis, orchestrated by yet not fully understood intricate signaling pathways in osteoblasts and endothelial cells. METHODS: In the...
BACKGROUND: Bone remodeling requires a complex interplay between osteogenesis and angiogenesis, orchestrated by yet not fully understood intricate signaling pathways in osteoblasts and endothelial cells. METHODS: In the present study, co-cultures of primary human osteoblasts and human umbilical vein endothelial cells (HUVEC) were compared with osteoblast cultures treated with dexamethasone (Dex), vascular endothelial growth factor (VEGF), their combination, or VEGF in the presence of Notch inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT). Cellular behavior was analyzed at morphological, gene expression, and protein levels to identify key regulators in the interplay between osteoblasts and endothelial cells. RESULTS: Dex and VEGF additively increased alkaline phosphatase (ALP) in osteoblast-HUVEC co-cultures, but not in osteoblast cultures. Furthermore, Dex reduced the receptor activator of nuclear factor κB ligand/osteoprotegerin (RANKL/OPG) ratio in osteoblasts. This effect was reversed in the presence of VEGF, but only in co-culture, indicating a direct action of endothelial cells, rather than VEGF itself, in stimulating RANKL and reducing OPG in osteoblasts. In addition, Notch signaling, specifically NOTCH1 and DLL4, was induced in response to VEGF solely in co-cultures. The presence of Notch inhibitor DAPT suppressed VEGF-induced stimulation of ALP but not RANKL/OPG ratio. CONCLUSIONS: Our findings provide novel evidence for the significant role of endothelial cells in bone remodeling, specifically in regulating ALP expression and activity of osteoblasts via the Notch signaling pathway and RANKL/OPG ratio independent of Notch. This study underscores the applicability and significance of multicellular tissue models for studying bone turnover processes in vitro, thereby reducing the reliance on animal testing.
Hypoimmune stem cells and islets: hype or a true breakthrough in diabetes treatment?
Shalaby KE, Abdelalim EM
Cell Mol Biol Lett · 2025 Oct · PMID 41039199 · Full text
Immune-resistant pancreatic islets hold great promise for advancing diabetes cell therapy. Two key approaches, hypoimmunogenic pluripotent stem cells (PSCs) and hypoimmunogenic cadaveric islets, aim to overcome immune re...
Immune-resistant pancreatic islets hold great promise for advancing diabetes cell therapy. Two key approaches, hypoimmunogenic pluripotent stem cells (PSCs) and hypoimmunogenic cadaveric islets, aim to overcome immune rejection in islet transplantation. Human PSCs provide a versatile source of insulin-producing cells, but immune rejection remains a major barrier. Recent advances in gene-editing technologies have enabled the modification of PSCs and cadaveric islets to reduce their immunogenicity. These cells can be engineered to express human leukocyte antigen (HLA)-negative profiles, while overexpressing immunoregulatory factors such as CD47, PD-L1, and HLA-G to evade T cell and natural killer (NK) cell immune-mediated responses. These modifications aim to generate "off-the-shelf" islet cell therapies compatible with a wide range of patients, potentially eliminating the need for immunosuppressants. However, ensuring long-term safety and functionality remains a challenge. Potential risks such as immune escape, viral infections, and tumorigenicity must be carefully addressed through additional safety measures. This review explores different approaches for generating hypoimmunogenic islets, recent advances in overcoming immune rejection, and key hurdles that need to be addressed for widespread clinical use for patients with diabetes. It also compares the potential benefits and limitations of hypoimmunogenic cadaveric islets versus hPSC-derived islets, providing insights into their future clinical applications.
Programmed cell death in triple-negative breast cancer.
Liu Y, He J, Chen J … +4 more , Chen T, Li W, Yang Z, Zeng F
Cell Mol Biol Lett · 2025 Oct · PMID 41039188 · Full text
Triple-negative breast cancer (TNBC) is a particularly aggressive and therapeutically challenging subtype of breast cancer, defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth fact...
Triple-negative breast cancer (TNBC) is a particularly aggressive and therapeutically challenging subtype of breast cancer, defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. This absence of actionable molecular targets contributes to its resistance to conventional treatments. This review provides an overview of the mechanistic functions, interrelated processes, and therapeutic implications of several programmed cell death (PCD) pathways-including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis-in the context of TNBC pathogenesis and treatment. A conceptual framework is proposed for leveraging these interconnected cell death pathways as a basis for novel targeted interventions. Given the complex interplay among various PCD forms characterized by shared features such as inflammation, mitochondrial dysfunction, and overlapping molecular mediators, this integrated network offers promising opportunities for combinatorial therapeutic strategies. Modulation of one cell death pathway may influence others, potentially amplifying therapeutic efficacy. Furthermore, these PCD pathways are highly relevant to immunotherapy outcomes, offering a foundation for synergistic treatment modalities. This review provides an in-depth analysis of the crosstalk between immune-based therapies and PCD, along with a comprehensive discussion of derived therapeutic approaches. However, tumor diversity, resistance mechanisms, and discrepancies between preclinical models and human physiology pose major challenges in applying these findings clinically. The overarching goal is to present innovative insights and strategies to enhance the clinical management of TNBC and ultimately improve patient outcomes.
FET fusion oncoproteins enrich SWI/SNF complex subtypes and interaction partners.
Lindén M, Andersson L, Albatrok H … +9 more , Canfjorden V, Jonasson E, Grönqvist K, Sjövall D, Jaako P, Crescitelli R, Fagman H, Åman P, Ståhlberg A
Cell Mol Biol Lett · 2025 Sep · PMID 40988026 · Full text
BACKGROUND: FET (FUS, EWSR1, and TAF15) fusion oncoproteins are characteristic for several sarcomas and leukemias, including myxoid liposarcoma and Ewing sarcoma. FET oncoproteins interact with the SWI/SNF chromatin remo...
BACKGROUND: FET (FUS, EWSR1, and TAF15) fusion oncoproteins are characteristic for several sarcomas and leukemias, including myxoid liposarcoma and Ewing sarcoma. FET oncoproteins interact with the SWI/SNF chromatin remodeling complex subtypes cBAF, PBAF, and GBAF, but their impact on SWI/SNF compositions, interactions, and downstream epigenetic effects remains elusive. METHODS: We employ a comprehensive immunoprecipitation and quantitative mass spectrometry approach to determine the impact of FET oncoproteins on SWI/SNF composition and their interactomes. Validation of complex composition and interaction partners is performed by glycerol gradient sedimentation assays and co-immunofluorescence analysis. Furthermore, we determine the differential chromatin accessibility and gene regulation in FET sarcomas using assay for transposase-accessible chromatin sequencing and RNA sequencing, respectively. RESULTS: Our data show that FET sarcomas have distinct SWI/SNF complex compositions, with different subunit paralogs and subtype-specific components that utilize distinct sets of interaction partners, including specific transcription factors. We show that FET oncoproteins cause no major disruption of the SWI/SNF complex composition. Instead, FUS::DDIT3-bound SWI/SNF complexes in myxoid liposarcoma cells are enriched in PBAF and GBAF components as well as most interaction partners. CONCLUSIONS: These data suggest that FET oncoproteins act together with fully assembled and functional SWI/SNF complexes and recruited interaction partners. Finally, our data reveal that the SWI/SNF compositions, interactomes, and epigenetic background contribute to the tumor type in FET sarcoma. Trial registration Clinical trial number: not applicable.
Atypical cadherin FAT1 promotes tumorigenesis by suppressing autophagic cell death in glioblastoma under hypoxia or nutrient stress.
Gupta Y, Goswami S, Arora M … +12 more , Malik N, Irshad K, Kundu A, Gowda SH, Kapoor M, Gupta S, Nag TC, Suri V, Suri A, Chattopadhyay P, Sinha S, Chosdol K
Cell Mol Biol Lett · 2025 Sep · PMID 40903775 · Full text
BACKGROUND: Autophagy, a conserved intracellular degradation process, plays dual roles in cancer, promoting survival under stress or mediating cell death through deregulated autophagy. Atypical cadherin FAT1 functions as...
BACKGROUND: Autophagy, a conserved intracellular degradation process, plays dual roles in cancer, promoting survival under stress or mediating cell death through deregulated autophagy. Atypical cadherin FAT1 functions as an oncogene or tumor suppressor in a context-dependent manner. Our previous work identifies the oncogenic role of FAT1 in glioblastoma. Deregulated autophagy has been documented in glioma. Here, we investigated the role of FAT1 in regulating autophagy and its implications for glioblastoma growth and progression. METHODS: CRISPR-Cas9 mediated FAT1 knockout was generated in glioblastoma (U87MG and LN229) and other cancers such as hepatocellular carcinoma (HepG2 and HUH7) and pancreatic adenocarcinoma (MIAPaca-2 and Panc-1) cells. The cell viability and growth under hypoxia ± serum deprivation were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, and Annexin V-FITC assays. Autophagy markers were assessed by quantitative polymerase chain reaction (qPCR), Western blot, immunocytochemistry (ICC), and immunohistochemistry (IHC). Autophagosomes were visualized by transmission electron microscopy (TEM), and puncta formation was analyzed by transfecting the cells with pEGFP-LC3. Autophagy flux was evaluated by analyzing p62/SQSTM1 levels, and the GFP/RFP ratio using pMRX-IP-GFP-LC3-RFP-LC3ΔG. In vivo, FAT1-knockout U87MG xenografts in nude mice were analyzed for tumor growth and autophagy marker expression. Surgically resected glioblastoma tumors from our hospital and The Cancer Genome Atlas (TCGA) dataset were analyzed for autophagy marker expression and patient survival correlations. RESULTS: FAT1-knockout glioblastoma (U87MG and LN229) cells demonstrated reduced survival and colony numbers under normoxia and hypoxia with serum deprivation, facilitated by autophagy-dependent cell death. These cells exhibited upregulated autophagy markers, increased LC3 puncta, autophagosomes, and autophagy flux. FAT1-knockout glioblastoma cells showed decreased total and phospho-mTOR levels. FAT1-knockout xenografts showed reduced tumor progression with increased LC3II, Beclin1, and autophagosomes. Human glioblastoma tumors and TCGA glioblastoma data revealed an inverse expression correlation of FAT1 with LC3B/Beclin1, tumors with high-FAT1/low-LC3B expression were associated with poor patient survival. FAT1 also regulated autophagy in hepatocellular and pancreatic cancers. CONCLUSION: Our findings indicate that FAT1 mediates pro-tumorigenic function by suppressing autophagic cell death in glioblastoma and other cancers. FAT1 may serve as a potential therapeutic adjuvant along with standard therapeutic regimens for treating cancers with high FAT1 expression having an oncogenic role.
A novel SWI/SNF complex promotes triple-negative breast cancer progression.
Sheng WY, Zhu Y, Liu SQ … +6 more , Huang QY, Qian WF, Cheng JL, Huang HH, Wang WJ, Meng Y
Cell Mol Biol Lett · 2025 Sep · PMID 40890601 · Full text
BACKGROUND: Triple-negative breast cancer (TNBC) is the most prevalent and fatal cancer affecting women worldwide. The SWI/SNF complexes exhibit the ability to selectively replace subunits, thereby enabling a wide range...
BACKGROUND: Triple-negative breast cancer (TNBC) is the most prevalent and fatal cancer affecting women worldwide. The SWI/SNF complexes exhibit the ability to selectively replace subunits, thereby enabling a wide range of epigenetic functions. As an accessory subunit of this complex, ARID1B is critically involved in modulating chromatin accessibility and transcriptional regulation. Nevertheless, its precise contribution to TNBC pathogenesis remains poorly understood. METHODS: ARID1B expression levels in TNBC were detected using immunofluorescence and real-time quantitative polymerase chain reaction (PCR). To investigate ARID1B's biological functions in TNBC, a series of in vitro assays were conducted, complemented by subcutaneous tumor xenograft models. Mass spectrometry analysis was employed to identify ARID1B-interacting proteins, while RNA-sequencing (RNA-seq) was performed to screen downstream target genes regulated by ARID1B. The transcriptional regulatory mechanism of ZNF382 mediated by ARID1B was further validated through dual-luciferase reporter assays and Chromatin immunoprecipitation (ChIP)-qPCR. To determine if ZNF382 knockdown could reverse the cellular effects of ARID1B, SMARCC2, and SMARCB1 inhibition, functional rescue experiments were conducted. RESULTS: We identified ARID1B as a notable E3 ubiquitin ligase gene associated with breast cancer prognosis, particularly serving as a risk prognostic factor in TNBC. Contrary to its previously reported function as an E3 ubiquitin ligase, we observed that ARID1B transcriptionally represses ZNF382 by forming a novel SWI/SNF complex with SMARCC2 and SMARCB1. This newly assembled complex promotes TNBC proliferation and migration, highlighting a previously unrecognized mechanism of ARID1B in cancer development. CONCLUSIONS: This research enhances the understanding of the intricate roles played by SWI/SNF complex components in TNBC and bridges the gap between the structural specificity of SWI/SNF assembly and the progression of cancer. These findings could potentially unveil novel therapeutic targets for TNBC, thereby advancing the development of more efficacious treatment approaches for this highly aggressive malignancy.
CCHCR1 links P-body proteins to the centrosome and is required for ciliogenesis through interacting with OFD1 and PCM1.
Zhang J, Wu Q, Zhang S … +2 more , Sze SCW, Li C
Cell Mol Biol Lett · 2025 Aug · PMID 40883668 · Full text
BACKGROUND: Processing bodies (P-bodies) are nonmembranous ribonucleoprotein (RNP) granules located in the cytosol that function as assembly hubs for RNA storage and degradation. Although there are reports indicating tha...
BACKGROUND: Processing bodies (P-bodies) are nonmembranous ribonucleoprotein (RNP) granules located in the cytosol that function as assembly hubs for RNA storage and degradation. Although there are reports indicating that certain P-body proteins are also present at the centrosome and participate in primary cilia development, how these P-body proteins localize to the centrosome remains unclear. In mammalian cells, coiled-coil alpha-helical rod protein 1 (CCHCR1) is localized to both the P-bodies and centrosomes, where it interacts with the P-body component enhancer of mRNA-decapping protein 4 (EDC4) as well as a range of centriolar satellite components, yet its cellular function remains poorly characterized. METHODS: Biotin identification (BioID) coupled with mass spectrometry, immunoprecipitation (IP), glutathione S-transferase (GST) pull-down, and acceptor bleaching fluorescence resonance energy transfer (AB-FRET) assay were used to explore and identify protein-protein interactions. Gene overexpression, RNA interference-based gene knockdown, CRISPR-Cas9-mediated gene knockout, and immunofluorescence (IF) were applied to elucidate the underlying molecular mechanism. RESULTS: We identified that CCHCR1 interacts with oral-facial-digital syndrome 1 protein (OFD1) via its C-terminal coiled-coil domain. The centrosomal localization of CCHCR1 is determined by OFD1 and pericentriolar materials 1 (PCM1). We also found that CCHCR1 recruits P-body proteins to the centrosome through interacting with EDC4 via its N-terminal coiled-coil domain. Depletion of either CCHCR1 or P-body components EDC4 and DEAD-Box Helicase 6 (DDX6) impairs ciliogenesis. CONCLUSIONS: CCHCR1 acts as a linker that recruits P-body proteins to the centrosome and is essential for cilia development. The recruitment of P-body proteins to the centrosome via CCHCR1 is also one of the mechanisms by which PCM1 and OFD1 are involved in ciliogenesis.
Radiation-sensitive circRNA promotes intestinal regeneration.
Cai H, Liang X, Ai S … +10 more , Sun H, Zhang X, Lu Q, Yang Q, Li Y, Zhao D, Zhang M, Ji K, Wang Y, Liu Q
Cell Mol Biol Lett · 2025 Aug · PMID 40883663 · Full text
BACKGROUND: The intestine is one of the most sensitive organs to ionizing radiation (IR), and radiation-induced intestinal injury (RIII) impacts the quality of life of patients undergoing radiotherapy. There are limited...
BACKGROUND: The intestine is one of the most sensitive organs to ionizing radiation (IR), and radiation-induced intestinal injury (RIII) impacts the quality of life of patients undergoing radiotherapy. There are limited early diagnostic biomarkers and specific medicines clinically approved for RIII. Therefore, we sought to identify new theranostic targets to prevent RIII and to facilitate the reestablishment of the intestinal epithelium. Circular RNAs (circRNAs) are widely appreciated as pervasive regulators of many diseases and multiple biological processes, while whether and how specific circRNAs are involved in radiation-induced intestinal injury remains largely unknown. METHODS: Differentially expressed circRNAs were analyzed and verified via RNA sequencing. The function of an intestine-specific circRNA (termed circDmbt1(3,4,5,6)) on cell proliferation, apoptosis, and DNA damage level after radiation was explored in vitro, and the underlying mechanism was further investigated. Ultimately, intestinal organoids and mice model were used to verify the role of circDmbt1(3,4,5,6) on radiation-induced intestinal injury. RESULTS: Primarily expressed in intestinal stem cells, CircDmbt1(3,4,5,6) was downregulated in mice intestines after 14 Gy abdominal radiation and showed timely relationship with intestinal injury level. CircDmbt1(3,4,5,6) promoted the proliferation and alleviated cell apoptosis and DNA damage level of intestinal epithelial cells and promoted organoids survival after radiation compared with control groups. In vivo experiments showed that compared with control groups, overexpression of circDmbt1(3,4,5,6) could increase intestinal length; enhance epithelial integrity and the percentage of proliferative cells, stem cells, paneth cells, and goblet cells; and promote intestinal adaption after radiation. Mechanistically, circDmbt1(3,4,5,6) protects intestines from IR via circDmbt1(3,4,5,6)/miR-125a-5p/STAT3. CONCLUSIONS: CircDmbt1(3,4,5,6), a novel promising RIII bio-marker, responses rapidly at the early stage after 14 Gy abdominal irradiation, and exogenous expression of circDmbt1(3,4,5,6) could promote intestinal fitness in RIII. We reveal that the circDmbt1(3,4,5,6)/miR-125a-5p/STAT3 axis is important to the regeneration of the intestinal epithelium after radiation-induced damage, providing a potential diagnostic and therapeutic target for RIII.
Growth differentiation factor 11 attenuates sepsis-associated acute kidney injury by reducing inflammation and coagulation via PGC-1α/Nrf2 activation.
Wang HW, Wu MM, Zhu MM … +9 more , Qin YY, Wang KQ, Wu CY, Zhang RR, Wang Y, Zhou C, Luo S, Lu CS, Pan JY
Cell Mol Biol Lett · 2025 Aug · PMID 40877798 · Full text
BACKGROUND: Patients with sepsis commonly endure severe renal dysfunction and damage, hastening to end-stage renal failure with high mortality, and effective treatment options are currently lacking. Growth differentiatio...
BACKGROUND: Patients with sepsis commonly endure severe renal dysfunction and damage, hastening to end-stage renal failure with high mortality, and effective treatment options are currently lacking. Growth differentiation factor 11 (GDF11), belonging to the transforming growth factor beta (TGF-β) superfamily, has shown therapeutic potential for numerous acute and chronic inflammatory conditions. Nevertheless, its function in sepsis-associated acute kidney injury (SAKI) remains unclear. PURPOSE: This study sought to explore GDF11's role in SAKI and determine the signaling pathways it modulates. METHODS: Alterations in GDF11 expression in the kidneys of mice with SAKI were analyzed. The influence of GDF11 knockdown and recombinant GDF11 (rGDF11) supplementation on cecal ligation and puncture (CLP)-induced SAKI in mice was determined. RNA sequencing, Western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and kit assays were performed to explore the underlying mechanisms. RESULTS: Tubular epithelial cells and macrophages in the kidneys of CLP-induced SAKI mice exhibited high levels of GDF11 expression. Moreover, gene silencing of GDF11 using adeno-associated virus (AAV) aggravated renal dysfunction, increased tubular damage, and augmented renal apoptosis in CLP-induced SAKI mice. In contrast, replenishment of rGDF11 significantly mitigated these adverse effects. Further studies indicated that GDF11 stimulated the nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated antioxidative pathways, primarily by inducing the expression of Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), which subsequently decreased excessive inflammation and coagulation. Additionally, these beneficial effects of GDF11 were largely diminished by AAV-mediated PGC-1α knockdown and depletion of Nrf2 in CLP-induced SAKI mice. CONCLUSIONS: In summary, these findings indicate that GDF11 is a potential therapeutic approach for SAKI and highlight the crucial role of PGC-1α/Nrf2 signaling in GDF11-mediated renal protection during SAKI.
NSUN2-tRNA-axis-regulated codon-biased translation drives triple-negative breast cancer glycolysis and progression.
Wang W, Ding Y, Zhao H … +3 more , Wang S, Huang J, Sun L
Cell Mol Biol Lett · 2025 Aug · PMID 40855521 · Full text
BACKGROUND: Epitranscriptomic data indicate that aberrant tRNA modifications in malignant diseases can promote tumor growth by facilitating oncogene translation. NSUN2, a 5-methylcytosine (m5C) methyltransferase of tRNA,...
BACKGROUND: Epitranscriptomic data indicate that aberrant tRNA modifications in malignant diseases can promote tumor growth by facilitating oncogene translation. NSUN2, a 5-methylcytosine (m5C) methyltransferase of tRNA, is elevated in an array of solid cancers, including triple-negative breast cancer (TNBC). However, it remains unclear how NSUN2 drives aggressive behavior and if NSUN2 could be an effective therapeutic target for TNBC. METHODS: Functional experiments, including RNA interference, lentivirus transduction, and in vivo xenograft models, were conducted to evaluate the role of NSUN2 in TNBC cell proliferation, metastasis, and chemoresistance. Ribosome sequencing (Ribo-seq), tRNA m5C bisulfite sequencing, and codon usage bias analysis were employed to explore the translational mechanisms underlying NSUN2-mediated tRNA modifications. Glycolysis assays and molecular docking were used to investigate metabolic reprogramming and protein interactions. RESULTS: NSUN2 was significantly upregulated in TNBC and correlated with poor patient prognosis. Mechanistically, NSUN2 mediates m5C modification of tRNA, enhancing the codon-frequency-dependent translation of key glycolysis-related genes, including ALDH3A2, ALDH7A1, HK1, and PFKM. Depletion of NSUN2 disrupted tRNA m5C modification, impairing the translation of these metabolic enzymes and suppressing glycolysis, which ultimately inhibited TNBC cell proliferation, migration, and invasion both in vitro and in vivo. Furthermore, NSUN2 overexpression conferred resistance to docetaxel, while its inhibition sensitized TNBC cells to docetaxel treatment. Clinically, elevated expression levels of NSUN2 and glycolysis-related genes were observed in docetaxel-resistant TNBC tissues, further supporting the role of NSUN2 in chemoresistance. CONCLUSIONS: This study identifies NSUN2 as a critical regulator of TNBC progression through tRNA m5C modification and codon-biased translation of glycolysis-related mRNAs. Our findings reveal a novel NSUN2-tRNA axis that orchestrates metabolic reprogramming and translational control in TNBC, offering a promising prognostic biomarker and therapeutic target.
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