Cell. Mol. Biol. Lett. [JOURNAL]
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200 papers
The promoting roles of GLP1R and GIPR in stemness maintenance and multiple lineage-specific differentiation of PDLSCs.
Shen Y, Zhang M, Yang T … +9 more , Wu Y, Qiu Y, Zhang L, Li F, Chen M, Chen Q, Wei W, Li H, Shen Y
Cell Mol Biol Lett · 2026 Feb · PMID 41673566 · Full text
BACKGROUND: Periodontal ligament stem cells (PDLSCs) hold great promise for periodontal regeneration therapy. However, their self-renewal and multilineage differentiation capabilities are often compromised by adverse fac...
BACKGROUND: Periodontal ligament stem cells (PDLSCs) hold great promise for periodontal regeneration therapy. However, their self-renewal and multilineage differentiation capabilities are often compromised by adverse factors in the periodontal microenvironment. Therefore, identifying novel therapeutic targets and elucidating the underlying molecular mechanisms to protect the proliferative and differentiation potential of PDLSCs is of significant importance. METHODS: PDLSCs were exposed to electronic cigarette extract and various common oral stressors to evaluate the expression of glucagon such as peptide 1 receptor (GLP1R) and gastric inhibitory polypeptide receptor (GIPR). PDLSCs isolated from patients with periodontitis and PDLSCs from a mouse periodontitis model were also analyzed. Functional studies were performed by GLP1R or GIPR knockdown, overexpression, and treatment with single or dual receptor agonists, followed by assessment of cell proliferation and multilineage differentiation capacities. Transcriptome (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA immunoprecipitation sequencing (RIP-seq) were applied to delineate downstream signaling pathways and RNA–protein interactions. Protein synthesis regulation was further investigated by immunoprecipitation of interferon induced protein with tetratricopeptide repeats (IFIT)-associated translation initiation factors. For in vivo validation, wild-type and GLP1R/GIPR double-knockout periodontitis mice were transplanted with CRISPR-Cas9 mCherry-labeled PDLSCs and treated with receptor agonists. Disease severity and PDLSC fate were evaluated by histology and lineage tracing. Finally, a questionnaire-based survey was conducted in 150 patients with periodontitis, including 74 individuals with long-term use (> 1 month) of GLP1R or GLP1R/GIPR dual agonists (e.g., semaglutide, liraglutide, tirzepatide), to assess their periodontal outcomes. RESULTS: GLP1R and GIPR expression were markedly downregulated in PDLSCs exposed to multiple stressors and in PDLSCs isolated from periodontitis specimens. RNA-seq, ChIP-seq, and RIP-seq identified downstream pathways and RNA–protein interactions implicated in receptor-mediated regulation. Functionally, GIPR agonism promoted PDLSC proliferation via activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, whereas GLP1R agonist enhanced multilineage differentiation capacity in vitro. Mechanistically, GLP1R knockdown induced robust upregulation of IFIT1/2/3, while GLP1R agonist suppressed IFIT expression. IFIT1/2/3 were shown to interact with eIF3C and to inhibit translation of differentiation-related mRNAs, linking GLP1R signaling to translational control of PDLSC fate. In vivo, transplantation experiments in both wild-type and GLP1R/GIPR double-knockout periodontitis mice demonstrated that single and dual receptor agonists significantly improved endogenous and exogenous PDLSC-mediated periodontal regeneration. Consistently, a clinical survey of 150 patients with periodontitis (74 receiving GLP1R or dual agonists) revealed significantly better periodontal staging and grading in treated individuals, with longer agonist exposure associated with greater improvement. CONCLUSIONS: Our findings uncover the different molecular roles of GIPR and GLP1R in self-renewal capacity and multipotency of PDLSCs, and open new avenues for developing therapeutic targets and strategies in oral tissue engineering and regenerative medicine.
TRMT6/TRMT61A-mediated tRNA mA modification enhances protein translation and activates the IRE1α-XBP1s pathway to promote anaplastic thyroid cancer progression.
Ding Y, Feng Z, Chen G … +3 more , Liu Y, Zhu Y, Cao K
Cell Mol Biol Lett · 2026 Feb · PMID 41667948 · Full text
BACKGROUND: Anaplastic thyroid cancer (ATC) is a highly aggressive malignancy with rapid progression and poor prognosis. Although N1-methyladenosine (m1A) modification has been implicated in cancer development, the speci...
BACKGROUND: Anaplastic thyroid cancer (ATC) is a highly aggressive malignancy with rapid progression and poor prognosis. Although N1-methyladenosine (m1A) modification has been implicated in cancer development, the specific role of tRNA m1A modification in ATC remains unclear. METHODS: An integrated multi-omics approach is employed, including m1A-MAP-tRNA-seq, tRNA-seq, RNA-seq, and Ribo-seq, complemented by functional assays such as tRNA aminoacylation assay, puromycin intake assay, and L-HPG staining. Additional experiments involved polysome profiling qRT-PCR, codon-switch assay, endoplasmic reticulum (ER)-tracker and TPE-MI staining, transmission electron microscopy, ChIP-qPCR, dual-luciferase reporter assay, and BODIPY staining to elucidate the underlying mechanism. RESULTS: TRMT6/TRMT61A is significantly upregulated in ATC. The complex promotes tumor cell proliferation and metastasis by enhancing the aminoacylation of specific tRNAs, thereby facilitating global protein translation. Elevated translation led to the accumulation of unfolded proteins in the ER, which activates the IRE1α–XBP1s pathway. Notably, m1A modification also increased IRE1α translation, further amplifying the pathway. Activation of the IRE1α–XBP1s pathway upregulates DGAT1 expression, which promotes triglyceride synthesis. CONCLUSIONS: Together, these findings reveal a previously unrecognized mechanism by which TRMT6/TRMT61A drives ATC progression through translational and metabolic reprogramming, identifying TRMT6/TRMT61A as a promising therapeutic target in ATC.
Sepsis alters NK cell transcriptional programs for stress, actin remodeling, and intracellular trafficking.
Lindner HA, de la Torre C, Velásquez SY … +4 more , Schulte J, Sticht C, Thiel M, Coulibaly A
Cell Mol Biol Lett · 2026 Feb · PMID 41639626 · Full text
BACKGROUND: Natural killer (NK) cells exert cytotoxicity against transformed and infected cells. In human sepsis, a suppressive NK cell receptor signature and defective effector molecule expression have been described. H...
BACKGROUND: Natural killer (NK) cells exert cytotoxicity against transformed and infected cells. In human sepsis, a suppressive NK cell receptor signature and defective effector molecule expression have been described. However, the transcriptional mechanisms underlying this phenotype remain poorly defined. METHODS: We analyzed microarray-based transcriptomic profiles of isolated peripheral NK cells from patients with sepsis, patients with systemic inflammatory response syndrome (SIRS), and presurgical controls. Enrichment analyses of canonical pathways, biological processes, and cellular compartments were performed. Differential gene expression was validated in an independent cohort using a multiplex branched-DNA assay. Functional signal transducer and activator of transcription (STAT) phosphorylation responses ex vivo and proliferation marker expression were assessed by flow cytometry in independent patient samples. RESULTS: NK cells from patients with sepsis displayed transcriptional signatures indicative of DNA replication stress, endoplasmic reticulum (ER) stress, altered cytoskeletal dynamics, and vesicle trafficking. Despite enrichment of proliferation-associated transcriptional programs, NK cells showed no increase in Ki-67 expression, indicating impaired proliferative activity. In contrast, NK cells from patients with SIRS exhibited downregulation of immune signaling pathways. CONCLUSION: This study identifies early stress-associated transcriptional programs and impaired subcellular organization in circulating NK cells during sepsis. Dysregulated DNA replication and ER stress responses, along with altered vesicle trafficking linked to impaired small guanosine triphosphatase (GTPase) signaling, may contribute to NK cell dysfunction in sepsis and may inform the development of NK cell-based immunotherapeutic strategies in critical illness.
TSP50 attenuates metabolic dysfunction-associated steatotic liver disease via SCD1 degradation-mediated suppression of hepatocyte lipogenesis.
Liang J, Luan Z, Jin R … +16 more , Su R, Ge J, Tian X, Niu C, Li J, Li X, Gao F, Song Z, Sun L, Wang G, Zheng L, Sun Y, Liu L, Bao Y, Wang S, Yang X
Cell Mol Biol Lett · 2026 Feb · PMID 41622160 · Full text
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to chronic liver disease worldwide, yet the molecular mechanisms driving its pathogenesis remain incompletely defined. A...
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to chronic liver disease worldwide, yet the molecular mechanisms driving its pathogenesis remain incompletely defined. Although dysregulated hepatic lipogenesis is a well-established driver of MASLD progression, the role of testes-specific protease 50 (TSP50)—an enzyme with demonstrated oncogenic functions in multiple cancers—in hepatic lipid metabolism and its potential involvement in the development of MASLD remains unexplored. METHODS: The study utilized the STelic Animal Model (STAM) along with high-fat/high-cholesterol plus fructose (HFF) and methionine-choline deficient (HFMCD) dietary models to evaluate the functional role of TSP50 in MASLD progression. Hepatocyte-specific knockout and AAV-mediated TSP50 reconstitution were performed to assess cell-autonomous effects. Mechanistic insights were gained through biochemical analyses of lipid metabolism pathways and protein interaction studies. RESULTS: TSP50 deficiency markedly accelerated MASLD progression across all experimental models, promoting hepatic steatosis, inflammation and fibrosis while increasing susceptibility to hepatocellular carcinoma (HCC). Conversely, TSP50 supplementation exerted protective effects against MASLD development. Furthermore, we identified a novel regulatory mechanism whereby TSP50 directly interacts with and degrades stearoyl-CoA desaturase 1 (SCD1) through its catalytic hydrolase activity, thereby suppressing de novo lipogenesis. The inhibitor of SCD1 rescued hepatic TSP50 knockout induced lipid accumulation and liver injury during MASLD. CONCLUSIONS: Our study reveals the role of TSP50 in hepatic lipid metabolism, identifying it as a novel regulator of hepatic de novo lipogenesis that exerts protective effects against MASLD through catalytic degradation of SCD1. These findings not only advance our understanding of MASLD pathogenesis but also offer novel insights for developing therapeutic strategies.
Role of LONP1 in human diseases: molecular mechanisms and therapeutic potential.
Li M, Wang A, Tang C … +3 more , Qiao Y, Zhang W, Wu Y
Cell Mol Biol Lett · 2026 Jan · PMID 41620670 · Full text
Mitochondria, the primary energy producers in eukaryotic cells, depend on an intricate protein quality control (PQC) system to preserve their functional integrity. Lon protease 1 (LONP1), an adenosine triphosphate (ATP)-...
Mitochondria, the primary energy producers in eukaryotic cells, depend on an intricate protein quality control (PQC) system to preserve their functional integrity. Lon protease 1 (LONP1), an adenosine triphosphate (ATP)-dependent serine protease localized in the mitochondrial matrix, maintains mitochondrial proteostasis through selective degradation of misfolded and oxidatively modified proteins. Beyond its proteolytic activity, LONP1 not only acts as a molecular chaperone facilitating protein folding but also directly binds to mitochondrial DNA (mtDNA), suggesting a multifunctional role in mitochondrial genome regulation. LONP1 is tightly regulated through multilayered mechanisms spanning transcriptional control, epigenetic modulation, and post-translational modifications. Emerging evidence establishes mechanistic links between LONP1 and the pathogenesis of various human diseases. In this review, we comprehensively summarize the structural features and multifunctional roles of LONP1, with particular emphasis on its disease-associated molecular mechanisms. We further evaluate existing pharmacological modulators of LONP1 activity, providing a theoretical basis for the development of new therapeutic strategies for related diseases.
Keratinization-related gene signature predicting survival and response to radiation in patients with HPV-negative head and neck squamous cell carcinoma via regulation of cornification and integrin signaling.
Lee MK, Joo H, Bae M … +8 more , Lee Y, Noh JK, Lee YC, Lee JW, Min S, Kong M, Ko SG, Eun YG
Cell Mol Biol Lett · 2026 Jan · PMID 41612193 · Full text
Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy associated with poor prognostic outcomes. Despite ongoing efforts to identify reliable biomarkers for prognosis, the clinical utility of...
Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy associated with poor prognostic outcomes. Despite ongoing efforts to identify reliable biomarkers for prognosis, the clinical utility of these markers remains limited owing to the need for further validation and deeper mechanistic insights. In this study, we developed and validated a novel keratinization-related gene signature (KRGS) to predict prognosis and radiation therapy (RT) response in human papillomavirus (HPV)-negative HNSCC using data from The Cancer Genome Atlas (TCGA). The 16-gene KRGS effectively stratified patients with HNSCC into two subgroups with significantly differing survival outcomes. KRGSlow, characterized by low KRGS expression, exhibited poorer survival and reduced sensitivity to RT, while KRGShigh, with high KRGS expression, was associated with more favorable survival outcomes and enhanced RT responsiveness. Functional validation, both in vitro and in vivo, demonstrated that keratinization activation through all-trans retinoic acid (ATRA) treatment upregulated the cornified envelope and sensitized HNSCC cells to RT. The enhanced response to RT was further associated with the upregulation of eight KRGS-related genes and increased expression of involucrin (IVL), a key regulator of terminal differentiation during cornification. Notably, the combination of ATRA and IR reduced radioresistance in HNSCC cells, which was linked to the downregulation of integrin alpha-1 (ITGA1) expression. These findings provide new insights into the role of keratinization in modulating radioresistance and suggest that KRGS-driven activation of keratinization, in combination with RT, may represent a promising therapeutic strategy to overcome resistance in HNSCC.
VPS34-IN1 potentiates STING-dependent activation in human CAL-1 cells.
Antas P, Machado MD, Leite-Pinheiro F … +15 more , Barros D, Ramalhinho C, Mendes A, Ferreira BH, Carvoeiro D, Mendes LF, Reverendo M, Duarte IF, Narita M, Su B, Argüello RJ, Nal B, Pierre P, Almeida CR, Gatti E
Cell Mol Biol Lett · 2026 Jan · PMID 41580642 · Full text
Inhibition of the phosphatidylinositol kinase vacuolar protein sorting 34 (VPS34) with the pharmacological compound VPS34-IN1 has a range of effects on the dynamics of endosomes. While VPS34 inhibition has been previousl...
Inhibition of the phosphatidylinositol kinase vacuolar protein sorting 34 (VPS34) with the pharmacological compound VPS34-IN1 has a range of effects on the dynamics of endosomes. While VPS34 inhibition has been previously suggested as a potential therapeutic approach for treating certain cancers, our findings indicate that it has minimal cytotoxic effects on the leukemic blastic plasmacytoid dendritic cell neoplasm (BPDCN) CAL-1. However, we also found that VPS34-IN1 interferes with the function of this plasmacytoid dendritic cell (pDC) line, by inhibiting Toll-like receptor (TLR)7 signaling. In contrast, VPS34-IN1 triggers activation of the stimulator of interferon genes (STING) and significantly enhances cellular response to the STING agonist 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) with increased expression of type I interferons (IFNs). Inhibition of protein synthesis by VPS34-IN1 appears to be central to this synergy with STING activation. Thus, despite their limited toxicity toward different cancer lines, VPS34-IN1 may represent a promising compound to promote expression of type I IFNs and thus antitumoral immunity.
Inhibition of the RORC/GPX4 mediated ferroptosis regulatory axis suppresses tumor growth and alleviates enzalutamide resistance in prostate cancer.
Li Y, Zhang B, Zhang Z … +6 more , Yan W, Wang H, Xu X, Lv A, Liao Z, Guo L
Cell Mol Biol Lett · 2026 Jan · PMID 41580593 · Full text
BACKGROUND: Patients with castration-resistant prostate cancer (CRPC) often develop resistance following long-term enzalutamide treatment. Building upon previous research, we aims to further explore the effect of ilicico...
BACKGROUND: Patients with castration-resistant prostate cancer (CRPC) often develop resistance following long-term enzalutamide treatment. Building upon previous research, we aims to further explore the effect of ilicicolin A (ili-A) on enzalutamide resistance and to elucidate the underlying resistance mechanisms. METHODS: Proliferation, migration, and invasion of prostate cancer (PCa) cells were evaluated by 5-ethynyl-2'-deoxyuridine (EdU) assays, colony formation, scratch, and Transwell. Cell Counting Kit 8 (CCK-8) was used to assess the efficacy of drug inhibition in CRPC cells. The expression of tumor cell apoptotic proteins and ferroptosis was assessed using western blot (WB) analysis. Coimmunoprecipitation (Co-IP) and proximity ligation assay (PLA) were used to identify the mechanism of interaction between ilicicolin A and ferroptosis. Tumor transplantation experiments with mice were conducted to confirm findings. RESULTS: Ili-A showed dose-dependent inhibition of PCa cells including C4-2B and 22Rv1 cell lines. The overexpression of the RORC gene activated the expression of ferroptosis-related proteins, such as FTH1, GPX4 and SLC7A11, and enhanced proliferation of PCa cells. WB experiments indicated that RORC upregulated AR and AR-V7. An enzalutamide-resistant C4-2B cell line revealed that RORC serves as a gene target for enzalutamide resistance. Finally, it was observed that ili-A could suppress CRPC cells proliferation by downregulating RORC expression, thereby promoting ferroptosis and enhancing the sensitivity to enzalutamide. CONCLUSIONS: Ili-A inhibited RORC expression, increased malondialdehyde (MDA) content, suppressed glutathione (GSH) production, released free Fe, increased reactive oxygen species (ROS), activated the ferroptosis pathway, enhanced enzalutamide sensitivity, and inhibited CRPC cell proliferation. Furthermore, ili-A enhances the interaction between ROR-γ and GPX4.
Cognitive-exercise dual-task training delays natural aging/D-galactose-induced cognitive decline in mice.
Zhu ZM, Dai TT, Zhang R … +4 more , Huang PL, Wu JL, Song L, Gong WJ
Cell Mol Biol Lett · 2026 Jan · PMID 41578175 · Full text
BACKGROUND: Cognitive–exercise dual-task training has been shown to enhance cognitive function through mechanisms such as suppression of chronic inflammation, reduction of oxidative stress, and enhancement of synaptic pl...
BACKGROUND: Cognitive–exercise dual-task training has been shown to enhance cognitive function through mechanisms such as suppression of chronic inflammation, reduction of oxidative stress, and enhancement of synaptic plasticity. However, the precise mechanisms underlying the ability of dual-task training to delay aging-related cognitive decline remain incompletely understood. METHODS: Aged male C57BL/6J mice were subjected to a 12-week intervention program consisting of cognitive training, exercise, or cognitive–exercise dual-task training. Cognitive and physical function were assessed using a battery of behavioral tests, including the open field test, elevated plus maze test, inverted grid test, wire hanging test, rotarod test, novel object recognition test, novel object localization test, eight-arm maze test, and Morris water maze test. Hippocampal aging and associated molecular changes were assessed using multiple techniques, including terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, Nissl staining, immunohistochemistry, immunofluorescence, flow cytometry, quantitative polymerase chain reaction, Western blotting, co-immunoprecipitation, and dual-luciferase reporter assays. In addition, we established in vitro models of cellular senescence using D-galactose, RNA overexpression/silencing models utilizing siRNA, and Ephrin type-B receptor 2 (EphB2) inducer/inhibitor models to explore specific molecular mechanisms. RESULTS: Age-related upregulation in microRNA (miR)-204 and downregulation in long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) were observed to disrupt Ephrin-B1 (EFNB1)/EphB2 interactions, leading to reduced cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway activation. These alterations were implicated in the pathogenesis of aging-related cognitive decline. Timely interventions, especially cognitive–exercise dual-task, were found to attenuate these phenomena, thereby delaying the progression of aging-related cognitive decline. CONCLUSIONS: Timely intervention during the aging process can effectively delay the progression of cognitive decline. The effects of cognitive–exercise dual-task training may surpass those of single-task interventions with either cognitive training or exercise alone.
Targeting the sirtuin 6-NF-κB p65 axis by 6-hydroxyhyoscyamine hydrobromide: a deacetylation-driven new therapy for diabetic wounds.
Chen J, Qin S, Xing Z … +4 more , Wan F, Yin J, Peng C, Li D
Cell Mol Biol Lett · 2026 Jan · PMID 41572148 · Full text
BACKGROUND: Diabetic wounds are a debilitating complication of diabetes mellitus with a high rate of amputation and mortality. 6-Hydroxyhyoscyamine hydrobromide (6-HH) is a belladonna alkaloid with smooth-muscle-relaxing...
BACKGROUND: Diabetic wounds are a debilitating complication of diabetes mellitus with a high rate of amputation and mortality. 6-Hydroxyhyoscyamine hydrobromide (6-HH) is a belladonna alkaloid with smooth-muscle-relaxing and microcirculation-enhancing properties, yet its role in diabetic wounds remains unknown. METHODS: In vivo, diabetic wounds were established in streptozotocin (STZ)-induced type 1 diabetic mice, high fat diet (HFD)/STZ-induced type 2 diabetic mice, and db/db diabetic mice to investigate the therapeutic effects of 6-HH, and skin samples were collected for hematoxylin and eosin (H&E) and Masson’s trichrome staining, immunofluorescence, RNA-seq analysis, and western blotting. In vitro, the mechanism of action of 6-HH on cytokines, nuclear factor kappa B (NF-κB) signals, and the interaction between sirtuin 6 (SIRT6) and p65 in lipopolysaccharide (LPS)-induced macrophages were detected by using enzyme-linked immunosorbent assay (ELISA), western blotting, reverse-transcription quantitative polymerase chain reaction (RT-qPCR), immunofluorescence, and immunoprecipitation, while molecular docking was used to evaluate the binding energy between 6-HH and SIRT6 protein. Coculture systems of THP-1 cells–human umbilical vein endothelial cells (HUVECs)/immortalized human keratinocytes (HaCaTs) were established to investigate the effects of 6-HH on cross-talk between macrophages and endothelial cells/keratinocytes. SIRT6-specific inhibitor Oss_128167 was applied in vitro and in vivo to verify the mechanism of 6-HH in diabetic wound healing. RESULTS: 6-HH exhibited excellent pro-healing effect in the three types of diabetic mouse model. RNA-seq analysis found that 6-HH recovered diabetic-induced aberrant expression changes of genes in the local wounds, especially those related to M1 macrophage polarization with downregulation of Toll-like receptor (TLR) signals and nicotinamide adenine dinucleotide phosphate (NADP+) nucleosidase activity. Molecular docking analysis found that 6-HH could effectively bind to the active site of the SIRT6 protein. Remarkably, decline of SIRT6 in M1 macrophages resulted in lysine hyperacetylation, while activation and stabilization of SIRT6 by 6-HH suppressed M1 macrophage polarization and hyperacetylation through inhibiting p65 transcription with deacetylation of p65Lys310 and H3K9, contributing to improve angiogenesis and re-epithelization through interaction between macrophages and endothelial cells/keratinocytes. However, pharmacological inhibition of SIRT6 reversed the action of 6-HH in macrophages and diabetic wounds. CONCLUSIONS: Collectively, deacetylase SIRT6 might be a direct pharmacological target of 6-HH that downregulates the hyperacetylated state of macrophages, thus contributing to diabetic wound healing.
Heat shock protein 90 stabilizes CD93 glycosylation to influence angiogenesis during diabetic wound healing.
Guo L, Liao Y, Hu Y … +5 more , Guo R, Cai L, Zhang N, Wang Z, Yang D
Cell Mol Biol Lett · 2026 Jan · PMID 41555217 · Full text
BACKGROUND: Angiogenesis, the formation of new blood vessels from preexisting vasculature, is often impaired in pathological conditions, such as a hyperglycemic environment. Angiogenesis is tightly regulated by a balance...
BACKGROUND: Angiogenesis, the formation of new blood vessels from preexisting vasculature, is often impaired in pathological conditions, such as a hyperglycemic environment. Angiogenesis is tightly regulated by a balance of proangiogenic and antiangiogenic factors. CD93, a glycoprotein expressed on endothelial cells (ECs), has been identified as a significant proangiogenic factor. However, the specific impact of its glycosylation, particularly O-GlcNAcylation, on endothelial cell function and angiogenesis remains entirely unexplored. Therefore, this study aimed to elucidate the role of CD93 glycosylation in angiogenesis and uncover the underlying molecular mechanism, especially under high glucose conditions. METHODS: siCD93 was used to evaluate the role of CD93 in endothelial cell angiogenesis. Tube formation, spheroid sprouting assays, Transwell assays, and adhesion assays were used to assess the angiogenic capability, migration, and adhesion, respectively. Co-immunoprecipitation coupled with mass spectrometry (Co-IP-MS) was employed to identify CD93-interacting proteins. A murine dorsal skin wound model was used to elucidate its role in angiogenesis during wound healing. RESULTS: siCD93 significantly impaired angiogenesis by inhibiting migration and adhesion without affecting proliferation or cell cycle in ECs. CD93 O-GlcNAcylation modulated its proangiogenic function, whereas high-glucose treatment downregulated both CD93 expression and its O-GlcNAcylation. CD93 overexpression partially rescued the angiogenic impairment induced by high glucose. In vivo studies further indicated that CD93 knockout exacerbated wound healing delay in diabetic wounds. Mechanistically, heat shock protein 90 (HSP90) interacted with the extracellular domain of CD93 to stabilize CD93 O-GlcNAcylation and protect it from ubiquitin-proteasomal degradation. The HSP90-CD93 interaction enabled CD93 to activate the downstream focal adhesion kinase (FAK) signaling pathway, thereby promoting angiogenesis. In vivo experiments further confirmed that HSP90 inhibition impaired the proangiogenic effects of recombinant CD93 protein (rCD93) in skin wound healing. CONCLUSIONS: CD93 promotes angiogenesis dependent on O-GlcNAcylation. Under high glucose, CD93 expression and its O-GlcNAcylation are downregulated, leading to impaired angiogenesis. Mechanistically, HSP90 interacts with CD93 to stabilize it against ubiquitin-proteasomal degradation, thereby maintaining O-GlcNAcylation homeostasis and activating the downstream FAK signaling pathway. Our findings identify the HSP90-CD93 interaction as a potential therapeutic target for angiogenesis-related disorders.
HNF4A P2 isoform alleviates kidney fibrosis by inhibiting dedifferentiation of proximal tubular cells through JAG1/NOTCH signaling.
Jiang G, Lu X, Cao R … +11 more , Zhang H, Gao Y, Lu K, Zhang L, Zhang G, Wu J, Xu B, Zhong J, Sun J, Chen M, Chen S
Cell Mol Biol Lett · 2026 Jan · PMID 41555216 · Full text
BACKGROUND: Tubulointerstitial fibrosis is a critical and irreversible process of chronic kidney disease. Dedifferentiated proximal tubular cells (PTCs) after injury are important for tubulointerstitial fibrosis. Hepatoc...
BACKGROUND: Tubulointerstitial fibrosis is a critical and irreversible process of chronic kidney disease. Dedifferentiated proximal tubular cells (PTCs) after injury are important for tubulointerstitial fibrosis. Hepatocyte nuclear factor 4 alpha (HNF4A) is the main regulatory factor for PTC differentiation. However, its role in PTC dedifferentiation and kidney fibrosis remains unclear. METHODS: To investigate the role of HNF4A in kidney fibrosis, bioinformatics analysis and in vivo models were used to evaluate its expression in kidney tissues. The mechanisms through which the HNF4A P2 isoform inhibits kidney fibrosis were examined by using both in vivo and in vitro models. RESULTS: In this study, we revealed that the sustained downregulation of HNF4A expression was a key characteristic of abnormally repaired PTCs after injury and was associated with cell dedifferentiation. It was confirmed that the HNF4A P2 isoform, rather than the P1 isoform, inhibited TGF-β1-induced PTC dedifferentiation. The activation of fibroblasts, which was induced by dedifferentiated PTCs through paracrine signalling, was also inhibited. In vivo experiments confirmed that HNF4A P2 was more effective than HNF4A P1 was in alleviating kidney fibrosis. Mechanistically, on one hand, HNF4A P2 antagonized the TGF-β1-induced dedifferentiation of PTCs by inhibiting the JAG1/NOTCH pathway. On the other hand, the distinct structure of HNF4A P2 from that of P1 made it unaffected by TGF-β1-activated SRC, allowing HNF4A P2 to perform transcriptional regulatory functions. CONCLUSIONS: These findings suggest that targeting the HNF4A P2 isoform could serve as a novel therapeutic strategy to alleviate kidney fibrosis.
Heterogeneity of glucose metabolism and uptake identifies distinct cancer cell and cancer stem cell phenotypes.
Tylichova Z, Krkoska M, Hrabal V … +3 more , Stenckova M, Vojtesek B, Coates PJ
Cell Mol Biol Lett · 2026 Jan · PMID 41547734 · Full text
BACKGROUND: Tumor cells show phenotypic heterogeneity, including a small subpopulation of cancer stem-like cells (CSCs) that are responsible for maintaining tumor growth and metastasis. Altered glucose metabolism is a ch...
BACKGROUND: Tumor cells show phenotypic heterogeneity, including a small subpopulation of cancer stem-like cells (CSCs) that are responsible for maintaining tumor growth and metastasis. Altered glucose metabolism is a characteristic feature of cancer cells, which often display increased aerobic glycolysis alongside mitochondrial oxidative respiration (the Warburg effect). However, there is evidence that CSCs exhibit distinct glucose metabolism compared with the tumor cell bulk, with increased mitochondrial activity and oxidative respiration. Thus, identifying individual cells with different modes of glucose metabolism may serve as a common identifier of CSCs, and these metabolic differences would allow selective therapeutic targeting. METHODS: We investigated the levels of enzymes involved in glycolysis and oxidative respiration, together with glucose uptake and mitochondrial membrane potential in individual cancer cells. These parameters were correlated with each other and with CSC markers. RESULTS: We show considerable heterogeneity of metabolic markers in individual tumor cells. Surprisingly, high glucose uptake correlates with high mitochondrial membrane potential, indicating that increased oxidative respiration and aerobic glycolysis coexist rather than showing an inverse correlation. We also show that colonies derived from cells with high mitochondrial membrane potential exhibit heterogeneous metabolic parameters, demonstrating that metabolic profiles are not hard-wired. Public gene expression profiling data indicated similar inconsistent metabolic features of CSCs. CONCLUSIONS: The data reveal inherent heterogeneity and plasticity of glucose metabolism and mitochondrial membrane potential in tumor cells, with evidence for a subpopulation that possesses both increased glucose uptake and increased mitochondrial membrane potential, with implications for therapeutic targeting of metabolism in cancer.
TGFβ pathway represses hepatic ribosome biogenesis and protein synthesis by regulating p70S6K-S6RP proteins.
Stavropoulos A, Stamatopoulou V, Pavlos E … +4 more , Manioudaki M, Sakellariou S, Stathopoulos C, Xilouri M
Cell Mol Biol Lett · 2026 Jan · PMID 41545854 · Full text
BACKGROUND: Transforming growth factor-beta (TGFβ)-superfamily signaling has been implicated in the regulation of hepatocyte growth and regeneration after acute or chronic liver injury. However, the precise mechanisms un...
BACKGROUND: Transforming growth factor-beta (TGFβ)-superfamily signaling has been implicated in the regulation of hepatocyte growth and regeneration after acute or chronic liver injury. However, the precise mechanisms underlying TGFβ signaling in the distinct hepatic cell types during the progression of liver fibrosis remain largely unknown. We aim to identify the downstream molecular mechanisms of TGFβ-signaling modulation on hepatocytes. METHODS: To modulate TGFβ-superfamily signaling in vivo, Smad3 or Smad7 were adenovirally overexpressed in mouse liver. Parallelly, hepatosphere cultures were treated with recombinant TGFβ1 and subjected to transcriptomic analysis. These data were compared with transcriptomes from Smad7-overexpressing livers. To broaden the analysis, publicly available RNA-seq datasets from TGFβ-treated hepatic stellate cells and hepatocellular carcinoma lines were meta-analyzed. Finally, human liver tissues from cirrhotic and healthy individuals were examined for fibrosis and ribosome biogenesis markers to validate murine findings. RESULTS: Acute hepatic overexpression of Smad3 induced a transient fibrotic phenotype in the mouse liver. In hepatosphere cultures, TGFβ1 treatment suppressed key components of ribosomal assembly, whereas Smad7 overexpression exerted the opposite effect in the mouse liver, thus highlighting ribosome biogenesis as a major cellular process negatively regulated by the TGFβ superfamily. Inhibition of TGFβ signaling via Smad7 increased hepatic protein content (a critical parameter for restoring hepatic homeostasis upon liver damage), activated the nucleolus, and prompted the production of ribosomal pre-mRNAs without affecting p53 levels. Mechanistically, SMAD7-mediated inactivation of TGFβ signaling triggered selectively the p70S6K-S6RP regulatory axis, independently of cellular myelocytomatosis oncogene (c-MYC), mechanistic target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK) pathways. Importantly, analysis of hepatic tissue from cirrhotic patients and controls unveiled a negative association between TGFβ signaling and ribosome biogenesis in fibrotic livers. Complementary meta-analysis of RNA-seq data demonstrated that TGFβ regulates ribosome biogenesis in a cell type-specific manner, suppressing it in hepatocytes while enhancing it in hepatic stellate cells, consistent with their distinct functional states and transcriptional landscapes. CONCLUSIONS: Collectively, our data reveal a SMAD-dependent regulatory role of TGFβ-superfamily signaling on hepatocytes that is tightly connected with hepatic growth to ensure proper energy homeostasis and metabolism. This is a critical regeneration parameter, which is closely related to the restoration of hepatic mass, especially following liver injury and fibrosis.
Methylation-induced silencing of AZGP1 enhances prostate cancer metastasis by stimulating tumoral glycolysis.
Li L, Luo J, Zhao L … +4 more , Tian L, Wang J, Cheng Y, Li X
Cell Mol Biol Lett · 2026 Jan · PMID 41535762 · Full text
BACKGROUND: Metastasis is the primary cause of mortality in patients with prostate cancer (PCa), yet effective treatments remain scarce. Identifying reliable biomarkers and understanding their underlying mechanisms is cr...
BACKGROUND: Metastasis is the primary cause of mortality in patients with prostate cancer (PCa), yet effective treatments remain scarce. Identifying reliable biomarkers and understanding their underlying mechanisms is crucial for advancing clinical management. METHODS: Firstly, we integrated single-cell and bulk transcriptomic data and employed the Scissor tool to characterize tumor cells with metastatic advantages (termed metastatic cells). Then, independent predictive genes for metastasis were identified through univariate and multivariate regression analyses. The role of hub genes in PCa metastasis was further validated using multiple large datasets, malignant phenotype experiments, in vivo metastatic models, and a clinical-sample-based immunohistochemical cohort. Further, we explored the metabolic characteristics related to hub genes through unbiased functional annotation, and validated the upregulated glycolysis by measuring L-lactic acid production, extracellular acidification rates (ECAR), and oxygen consumption rates (OCR). Finally, multi-omics data were employed to investigate the promoter-methylation-dependent regulation of alpha-2-glycoprotein 1 (AZGP1) transcription, with methylation confirmed through PCa cell-based methylation-specific PCR (MSP) assays. RESULTS: AZGP1 was identified as an independent protective predictor of metastasis, which was validated in vitro and in vivo. Metabolic functional annotation revealed that glycolysis was upregulated in AZGP1-positive luminal cells. Consistently, overexpression of AZGP1 in PCa cells was associated with lower L-lactic acid levels, reduced ECAR, and increased OCR. In addition, DNA methylation at the cg26429636 region was linked to decreased transcriptional expression of AZGP1. MSP assays revealed an unmethylated pattern in PCa cells with high AZGP1 expression, and higher methylation levels in AZGP1-low cells. CONCLUSIONS: Promoter methylation of AZGP1 leads to reduced transcriptional expression, thereby promoting glycolysis in tumor cells and facilitating metastasis. The detection of AZGP1 methylation levels offers a valuable reference for dynamic surveillance of PCa metastasis.
Mitochondria-endoplasmic reticulum contact sites in hepatocytic senescence.
Kumar P, Hassan M, Tacke F … +1 more , Engelmann C
Cell Mol Biol Lett · 2026 Jan · PMID 41521283 · Full text
Inter-organelle communication via membrane contact sites (MCSs) is essential for the efficient functioning of eukaryotic cells, facilitating coordination among approximately 20 distinct organelles, each with unique metab...
Inter-organelle communication via membrane contact sites (MCSs) is essential for the efficient functioning of eukaryotic cells, facilitating coordination among approximately 20 distinct organelles, each with unique metabolic profiles. Among these interactions, mitochondria-endoplasmic reticulum (ER) contacts (MERCs) are particularly significant, encompassing about 5% of the mitochondrial surface. Key proteins involved in MERCs include inositol 1,4,5-trisphosphate receptor (IP3R), voltage-dependent anion channel (VDAC), glucose-regulated protein 75 (GRP75), Sigma1 receptor (Sig-1R), vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), protein deglycase DJ-1, and protein tyrosine phosphatase interacting protein 51 (PTPIP51), with new proteins continually being identified for their roles in these structures. At these contact sites, metabolic exchanges involve calcium (Ca), lipids, reactive oxygen species (ROS), and proteins. MERCs enable efficient molecular exchanges through temporary bridges mainly formed by the ER, the organelle with the largest surface area. These contacts are crucial for maintaining mitochondrial dynamics, which is essential for cellular homeostasis, and they are notably impacted in pathological states such as metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver diseases (ALD), and viral hepatitis. Dysfunctional MERCs can lead to mitochondrial fragmentation, increased ROS production, impaired autophagy, and disrupted protein trafficking, thereby exacerbating senescence and cellular aging. Senescence is a cell fate initiated by stress, characterized by stable cell-cycle arrest and a hypersecretory state, and is an underlying cause of aging and many chronic conditions, including liver diseases. The hallmarks of senescence-such as macromolecular damage, cell cycle withdrawal, deregulated metabolism, and a secretory phenotype-are well established. However, recent studies have demonstrated that senescence is a heterogeneous process, with molecular markers varying according to the stressors that induce it. This review focuses on the functional aspects of MERCs in hepatic senescence and their impact on liver diseases, and explores the potential of targeting MERCs to address hepatocytic senescence.
SLC25A11-mediated reprogramming of mitochondrial redox state and lipid peroxidation confers NRF2-dependent ferroptosis resistance in biliary tract cancer.
Lin YY, Kuo HH, He ZJ … +9 more , Chung HY, Kim CH, Pan YR, Wu MJ, Chan MH, Yeh CN, Chiang NJ, Chen MH, Chang YC
Cell Mol Biol Lett · 2026 Jan · PMID 41514409 · Full text
BACKGROUND: Biliary tract cancer is a group of highly heterogeneous and metastatic malignancies of the biliary tract. Current clinical treatment strategies and diagnostic methods need further improvement to effectively m...
BACKGROUND: Biliary tract cancer is a group of highly heterogeneous and metastatic malignancies of the biliary tract. Current clinical treatment strategies and diagnostic methods need further improvement to effectively manage this disease. METHODS: We performed multiomics integrative and in silico analyses of selected SLC25 family members. Cell models with SLC25A11 overexpression or knockdown can be used for various biological function assays and cell imaging. Animal models and clinical specimens can be used to evaluate prognosis and treatment. RESULTS: SLC25A11 inhibition significantly reduced cell migration and proliferation both in vitro and in vivo. In addition, loss of SLC25A11 leads to accumulation of TCA-related metabolites, alters mitochondrial homeostasis, and reduces mitochondrial membrane potential. In addition, we confirmed that lipid peroxidation and lipid ROS aggregation in mitochondria by SLC25A11-knockdown model. Based on our RNA sequencing data, inhibition of SLC25A11 reduces NRF2 expression and translocation, resulting in loss of interaction affinity with the ferroptosis suppressor FSP1 and subsequent reactivation of the ferroptosis machinery. We also showed that low levels of SLC25A11 and knockdown models can activate lipid peroxidation and related molecules ACSL4, LPCAT3, and PEBP1, further inducing ferroptosis. Furthermore, recruitment of ferrostatin-1 (Fer-1) antagonizes the ferroptosis state by reducing lipid peroxidation and blocking the expression levels of these related molecules. CONCLUSIONS: Bringing all the evidence together, we added several important insights between ferroptosis and biliary tract cancer. We raised that SLC25A11 will serve as a novel prognostic factor and treatment strategy for biliary tract cancer.
The neuro-immune insights of itch: peripheral mechanisms and central glial contributions.
Li Z, Yu N, Feng S … +3 more , Wang X, Chu YX, Liu X
Cell Mol Biol Lett · 2026 Jan · PMID 41495658 · Full text
Itch is a common symptom of inflammatory, systemic, and neurological conditions and is often driven by persistent neuroinflammatory processes. This review explores the intricate mechanisms underlying itch, focusing on in...
Itch is a common symptom of inflammatory, systemic, and neurological conditions and is often driven by persistent neuroinflammatory processes. This review explores the intricate mechanisms underlying itch, focusing on interactions among sensory neurons, immune mediators, and glial cells. Key peripheral pathways include activation of pruriceptors by histamine, interleukins, and chemokines, as well as inflammatory pathways dependent on Toll-like receptors (TLRs). These pathways promote the release of mediators such as interleukin-6 (IL-6) and C–C motif chemokine ligand 2 (CCL2). In the spinal cord, astrocytes and microglia contribute to itch amplification by releasing proinflammatory cytokines and activating signaling pathways such as signal transducer and activator of transcription 3 (STAT3) and TLR4. These processes drive central sensitization and facilitate the transition from acute to chronic itch in conditions such as atopic dermatitis, psoriasis, and allergic contact dermatitis. By summarizing advances in neuroimmune crosstalk and glial–neuronal interactions, this review identifies potential molecular targets for therapeutic strategies aimed at alleviating itch and improving patient outcomes.
Targeting integrin αVβ3-Ptgs2-mTOR signaling rescues bone formation in osteoporosis: from molecular mechanism toward therapy.
Chen C, Gu J, Yang C … +6 more , Yang F, Liu Z, Wen L, Chen R, Geng B, Xia Y
Cell Mol Biol Lett · 2026 Jan · PMID 41495647 · Full text
BACKGROUND: Integrin αVβ3, a key ECM receptor, is essential for bone metabolism, yet its role in postmenopausal osteoporosis (PMOP) remains unclear. This study investigates the molecular mechanisms by which integrin αVβ3...
BACKGROUND: Integrin αVβ3, a key ECM receptor, is essential for bone metabolism, yet its role in postmenopausal osteoporosis (PMOP) remains unclear. This study investigates the molecular mechanisms by which integrin αVβ3 regulates osteoblast function and bone homeostasis in PMOP. METHODS: Using clinical samples, OVX mice, and in vitro models, we analyzed integrin αVβ3 expression and its impact on osteogenesis. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated knockout, multi-omics profiling, and protein interaction assays (Co-IP, BLI, and structural modeling) were employed to dissect the underlying pathway. An AAV9-based in vivo overexpression system was developed to evaluate therapeutic potential. RESULTS: Integrin αVβ3 was downregulated in PMOP patients and OVX mice, correlating with osteoblast dysfunction and reduced bone formation. Mechanistically, integrin αVβ3 deficiency upregulated Ptgs2, which directly bound to mammalian target of rapamycin (mTOR) via a hydrogen bond between Ptgs2-Glu52 and mTOR-Ser2159, inhibiting mTOR phosphorylation. This suppression disrupted mTORC1-S6K/4EBP1 signaling, impairing osteoblast proliferation and survival. Notably, AAV9-mediated integrin αVβ3 overexpression rescued bone loss in OVX mice. CONCLUSIONS: Our findings unveil a novel integrin αVβ3–Ptgs2–mTOR axis in PMOP pathogenesis: estrogen deficiency reduces integrin αVβ3, enabling Ptgs2-mediated mTOR inhibition and osteogenic decline. This study identifies integrin αVβ3 as a potential therapeutic target to restore bone formation in osteoporosis.
Many faces of mammalian NSD methyltransferases.
Tiukacheva EA, Vassetzky Y, Razin SV … +2 more , Fang D, Ulianov SV
Cell Mol Biol Lett · 2026 Jan · PMID 41495645 · Full text
Nuclear receptor-binding SET domain (NSD) proteins have been initially described as methyltransferases specific to lysine-36 in histone H3 and associated with active chromatin. However, their role in the regulation of tr...
Nuclear receptor-binding SET domain (NSD) proteins have been initially described as methyltransferases specific to lysine-36 in histone H3 and associated with active chromatin. However, their role in the regulation of transcription and in overall cellular physiology is much more complex, especially in mammals. The emerging diversity of their targets and, accordingly, the processes in which NSD proteins are involved, shows the importance of their noncanonical functions. A wide functionality apparently requires a complicated control system ensuring proper spatial and temporal activation of NSD methyltransferases. In this review, we discuss the role of NSD proteins in transcription, genome topology, mitosis, oncogenesis, immunity, DSB repair, and known mechanisms regulating their activity.
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