Cell. Mol. Biol. Lett. [JOURNAL]
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200 papers
The role of ECM mechanics in cancer mechanotransduction through unraveling the molecular machinery of integrins, FAK, and YAP signaling.
Hassan N, Greve B, Götte M
Cell Mol Biol Lett · 2026 Jun · PMID 42265604 · Full text
Mechanotransduction, the process by which cells convert mechanical stimuli into biochemical signals, is fundamental for maintaining tissue homeostasis and regulating physiological functions. The extracellular matrix (ECM...
Mechanotransduction, the process by which cells convert mechanical stimuli into biochemical signals, is fundamental for maintaining tissue homeostasis and regulating physiological functions. The extracellular matrix (ECM) serves as a critical mediator of mechanotransduction, with its mechanical properties influencing cellular behaviour and function through complex molecular machinery. This comprehensive review examines the role of ECM mechanics in disease mechanotransduction, focusing on the molecular machinery of integrins, focal adhesion kinase (FAK) and YAP signaling pathways. We explore the structure and composition of the ECM, including detailed analysis of key components such as collagens, elastin, glycoproteins, proteoglycans, hyaluronic acid and matrix metalloproteinases. The review elucidates how integrins function as key mediators of mechanotransduction, the role of FAK in signal transduction, and the mechanosensitive functions of YAP/TAZ signaling. We examine the intricate crosstalk between these mechanotransduction pathways and their dysregulation in cancer. Finally, we discuss emerging therapeutic strategies targeting mechanotransduction pathways and the challenges and opportunities for translating mechanotransduction research into clinical interventions. Understanding these complex mechanotransduction networks is crucial for developing novel therapeutic approaches to treat diseases characterized by altered tissue mechanics and dysregulated cellular responses to mechanical cues.
Chlorogenic acid mitigates calcium oxalate monohydrate crystal-induced epithelial-to-mesenchymal transition in renal epithelial cells via suppression of HSP60 expression and p38 signaling.
Peerapen P, Phuangkham S, Boonmark W … +1 more , Thongboonkerd V
Cell Mol Biol Lett · 2026 Jun · PMID 42265585 · Full text
BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a prominent process involved in kidney fibrosis. Calcium oxalate monohydrate (COM), a crystalline composition predominantly found in renal stones, is one of the k...
BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a prominent process involved in kidney fibrosis. Calcium oxalate monohydrate (COM), a crystalline composition predominantly found in renal stones, is one of the known stimuli that can trigger the EMT process. Chlorogenic acid (CGA), a phenolic hydroxycinnamate naturally found in several plants (especially coffee beans), has several health benefits, including antifibrotic properties. However, the mechanisms underlying its preventive effects against COM-induced EMT in renal epithelial cells remain unclear. METHODS: Herein, Madin-Darby canine kidney (MDCK) renal epithelial cells were exposed to COM crystals without or with CGA pre-/cotreatment and were subjected to various assays, including morphological examination, measurement of cell spindle index, transepithelial resistance (TER) measurement, immunofluorescence staining of EMT markers, and western blotting of p38 signaling proteins. Additionally, label-free quantitative proteomics using nanoLC-ESI-LTQ-Orbitrap MS/MS and functional enrichment analyses were carried out, followed by functional validation of the essential role of heat shock protein 60 (HSP60) using a small interfering RNA (siRNA)-based knockdown method. RESULTS: As expected, COM induced the EMT process as shown by increases in spindle index and mesenchymal marker (vimentin) but decreases in TER and epithelial marker (ZO-1). Mechanistically, these changes were accompanied with activation of p38 signaling. However, CGA pre-/cotreatment successfully prevented all these COM-induced changes. Label-free quantitative proteomics revealed significantly altered levels of 167 cellular proteins caused by COM. Among these, 55 proteins were completely preserved by CGA. Protein-protein interaction network illustrated HSP60 as a hub of these interacting proteins. While COM increased the HSP60 level, CGA successfully preserved this protein at its basal level. Moreover, knockdown of HSP60 expression by small interfering RNA could also prevent COM-induced EMT and p38 activation. CONCLUSIONS: These data indicate that CGA mitigates COM-induced EMT via suppression of HSP60 expression and p38 signaling activated by COM crystals.
GPNMB-ECD drives acquired resistance to osimertinib in NSCLC via inducing tumor cell cytoskeletal reorganization.
Zhang M, Wang JQ, Yang X … +5 more , Liu WY, Huang YT, Wen CJ, Chen D, Wu LX
Cell Mol Biol Lett · 2026 Jun · PMID 42260371 · Full text
BACKGROUND: Acquired resistance constitutes a major obstacle to the efficacy of osimertinib therapy in nonsmall-cell lung cancer (NSCLC), yet its underlying mechanisms remain incompletely understood. While the soluble ex...
BACKGROUND: Acquired resistance constitutes a major obstacle to the efficacy of osimertinib therapy in nonsmall-cell lung cancer (NSCLC), yet its underlying mechanisms remain incompletely understood. While the soluble extracellular domain of GPNMB (GPNMB-ECD) is recognized as a driver of tumor progression, its involvement in acquired resistance to osimertinib remains unknown. PURPOSE: This study aimed to investigate the role of GPNMB-ECD in acquired osimertinib resistance in NSCLC. METHODS: The expression dynamics of GPNMB in osimertinib-sensitive (OS) and osimertinib-resistant (OR) NSCLC tissues and cell lines were profiled using single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq, respectively. Full-length GPNMB and GPNMB-ECD levels in tumor tissues and patient plasma were assessed by immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). In vitro, the impact of GPNMB-ECD on osimertinib sensitivity was evaluated using CCK-8, colony formation, flow cytometry, and transwell assays. Correspondingly, in vivo effects were investigated in nude mouse models of subcutaneous and pulmonary metastasis. The underlying mechanisms were explored through co-immunoprecipitation (Co-IP), immunofluorescence, and transmission electron microscopy (TEM). Finally, the therapeutic efficacy of the anti-GPNMB-ECD antibody was evaluated in humanized patient-derived xenograft (huPDX) models. RESULTS: Tumor cells exhibited elevated GPNMB expression in OR tissues compared with OS controls and emerged as the primary source of GPNMB-ECD within the OR TME. Plasma levels of GPNMB-ECD were substantially higher in patients with OR NSCLC compared with patients with OS NSCLC, suggesting this marker as a potential indicator of acquired resistance and poor prognosis. Functional studies confirmed that GPNMB-ECD promotes osimertinib resistance both in vitro and in vivo. Mechanistically, GPNMB-ECD engages syndecan-4 (SDC4) on tumor cells, triggering SDC4 phosphorylation, F-actin reorganization, and Yes-associated protein (YAP) nuclear translocation, thereby upregulating pro-tumorigenic genes and reducing osimertinib sensitivity. Crucially, anti-GPNMB-ECD antibodies restored osimertinib sensitivity in huPDX models established from human NSCLC tumors. CONCLUSIONS: Our findings define GPNMB-ECD-driven resistance as a novel paradigm in NSCLC and identify a viable precision therapeutic strategy to overcome it.
Heterogeneity of macrophages in PD-1/PD-L1 inhibitor therapy: a single-cell perspective.
Wu J, Zhou D, Jiang K … +5 more , Li Z, Yao Y, Rao S, Yang X, Luo D
Cell Mol Biol Lett · 2026 Jun · PMID 42252409 · Full text
Therapeutic blockade of the PD-1/PD-L1 signaling pathway is the focus of tumor immunotherapy. However, drug resistance and irAEs induced by PD-1/PD-L1 inhibitors have emerged as major limitations affecting survival outco...
Therapeutic blockade of the PD-1/PD-L1 signaling pathway is the focus of tumor immunotherapy. However, drug resistance and irAEs induced by PD-1/PD-L1 inhibitors have emerged as major limitations affecting survival outcomes in patients with cancer. Macrophages are not only the core immune cells that regulate tumor progression and metastasis, but also the key factors that affect the therapeutic effect of PD-1/PD-L1 inhibitors, thus showing significant clinical value in optimizing immunotherapy strategies. scRNA-seq technology has provided powerful analytical tools and precise biological insights to decipher macrophage heterogeneity, further elucidating disease-specific macrophage subpopulations with distinct gene signatures and functional plasticity during PD-1/PD-L1 blockade therapy. These advances have paved the way for better understanding the mechanisms underlying immunotherapy-induced toxicities and identifying novel predictive biomarkers. Herein, we comprehensively summarize the multifaceted functional roles of macrophages in PD-1/PD-L1 inhibitor-mediated antitumor efficacy, drug resistance and irAEs from a single-cell perspective, and the potential value of targeting macrophages to improve the accuracy of immunotherapy.
ZNF662 inhibits oncogenesis through NUPR1/p53 signaling pathway in epithelial ovarian cancer and is regulated by hsa-miR-429.
Huang Z, Fu H, Li L … +6 more , Liao W, Zhang J, Tang Q, Huang M, Xiang T, Tang L
Cell Mol Biol Lett · 2026 Jun · PMID 42243650 · Full text
BACKGROUND: Epithelial ovarian cancer (EOC) represents the most lethal malignancy of the female reproductive system, though its etiology and pathogenesis remain incompletely characterized. The Krüppel-associated box doma...
BACKGROUND: Epithelial ovarian cancer (EOC) represents the most lethal malignancy of the female reproductive system, though its etiology and pathogenesis remain incompletely characterized. The Krüppel-associated box domain zinc finger protein (KRAB-ZNF) family, the largest transcription factor family in mammals, plays critical roles in malignant tumor development and progression. This study aimed to investigate the clinical significance and molecular mechanisms of ZNF662 in EOC pathogenesis. METHODS: ZNF662 expression patterns and their association with clinicopathological features and prognosis were analyzed using integrated bioinformatics (The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), CSIOVDB, Kaplan-Meier Plotter) and clinical tissue specimens. Functional impacts on proliferation, migration, invasion, apoptosis, and cell cycle progression were assessed then. Mechanistic studies delineating upstream regulators and downstream effectors employed transcriptome sequencing, dual-luciferase reporter assays, chromatin immunoprecipitation (ChIP), and functional validation experiments. RESULTS: ZNF662 expression was downregulated in ovarian cancer tissues, correlating with advanced tumor stage, ascites presence, and poor overall survival. Functional assays demonstrated that ZNF662 suppressed proliferation, migration, and invasion of ovarian cancer cells while promoting apoptosis and inducing G0/G1 cell cycle arrest. Bioinformatics analysis and dual-luciferase reporter assays confirmed that hsa-miR-429 directly binds to the 3'-untranslated region (UTR) of ZNF662, downregulating its expression and promoting malignant behaviors. Transcriptomic and mechanistic validation revealed that ZNF662 transcriptionally represses NUPR1 and activates the p53 signaling pathway, thereby inhibiting the malignant phenotype of EOC. CONCLUSIONS: The hsa-miR-429/ZNF662/NUPR1/p53 pathway axis critically regulates EOC pathogenesis. ZNF662 represents a promising diagnostic biomarker and therapeutic target for EOC.
Phosphoproteomic profiling reveals post-translational dysregulation in Huntington's disease patient-derived neurons.
Danics L, Muralidharan C, Varga Á … +16 more , Rezeli M, Gil J, Abbas AA, Pap Á, Park AS, Cserhalmi M, Legault EM, Sőth Á, Jamniczky D, Zsoldos R, Barker RA, Róna G, Drouin-Ouellet J, Markó-Varga G, Darula Z, Pircs K
Cell Mol Biol Lett · 2026 Jun · PMID 42231151 · Full text
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene. Although transcriptomic and proteomic changes have been characterized in patient-derived neurons, t...
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene. Although transcriptomic and proteomic changes have been characterized in patient-derived neurons, the contribution of post-translational modifications, such as phosphorylation, remains poorly understood. Here, we present the first phosphoproteomic analysis by mass spectrometry (P-MS) of human induced neurons (iNs) directly reprogrammed from HD patient fibroblasts. We identified 177 phosphopeptides with significantly altered abundance in HD-iNs, mapping to phosphoproteins associated with key signaling pathways known to be affected in HD, such as splicing and autophagy. By integrating P-MS data with previously published proteomic and transcriptomic data from the same donors, we identified distinct subsets of ON-OFF phosphopeptides that exhibited a complete loss of phosphorylation in either HD- or control-iNs, without corresponding changes at the RNA or protein level. An exception was MXRA8, previously described in glial cells as a mediator of blood-brain barrier integrity and astrocyte-mediated neuroinflammation. This protein showed increased protein abundance despite the absence of phosphorylation in HD-iNs, suggesting a compensatory mechanism. In addition, MXRA8 showed altered protein-protein interactions with lysosomal and metabolic regulators in HD-iNs, highlighting its potential role in autophagy impairment as well as in neurovascular dysfunction. These findings uncover a distinct layer of post-translational dysregulation in HD, suggesting that phospho-switch proteins such as MXRA8 may be candidate effectors of pathology, and thus, site-specific phosphorylation loss may contribute to impaired signaling and proteostasis in human HD neurons.
Deorphanisation and functional characterisation of OATP5A1 as transport protein for amino acids and vitamins.
Kohlmann E, Schmid NK, Gessner A … +2 more , Fromm MF, König J
Cell Mol Biol Lett · 2026 Jun · PMID 42231149 · Full text
BACKGROUND: Transport proteins are important for the uptake, distribution and elimination of endogenous substances and drugs, and therefore essential for, e.g., cellular metabolism or drug effects. While the export of su...
BACKGROUND: Transport proteins are important for the uptake, distribution and elimination of endogenous substances and drugs, and therefore essential for, e.g., cellular metabolism or drug effects. While the export of substrates out of cells is mediated by ATP-binding cassette (ABC) transporters, SLC (solute carrier) transporters are mainly responsible for the uptake into cells. In contrast to most well-characterised ABC transporters, many SLC transporters have been studied insufficiently. Such transporters are called orphan transporters. Despite the fact that the SLC21/SLCO family contains several important transporters for widely prescribed drugs, one of its family members, OATP5A1 (SLCO5A1), is such an orphan transporter. OATP5A1 is ubiquitously expressed throughout the body, including expression in the brain, heart, intestine and various cancerous tissues. However, no substrates have been characterised for this transporter to date. METHODS: Using stably-transfected HEK293 cells overexpressing human OATP5A1 (HEK-OATP5A1) and the respective control cells (HEK-VC), we investigated known substrates of other OATP family members as potential OATP5A1 substrates. Furthermore, an untargeted metabolomics analysis of both cell lines was performed after incubation with human plasma. Candidate substances were further characterised as substrates of OATP5A1. RESULTS: After characterisation of the stably-transfected HEK-OATP5A1 cells, uptake assays and untargeted metabolomics analysis identified the hormone conjugate estrone-3-sulfate, the amino acids glutamine, glycine and tyrosine, the vitamins pantothenic acid (vitamin B) and thiamine (vitamin B) and the nucleotide thymine as potential OATP5A1 substrates. While estrone-3-sulfate, tyrosine and thiamine were further characterised as uptake substrates, glutamine and glycine were exported by OATP5A1. Moreover, pantothenic acid and thymine inhibited OATP5A1-mediated tyrosine uptake. For estrone-3-sulfate, tyrosine and thiamine, kinetic transport parameters (K values) of 102.2 µM, 169.9 µM and 15.6 µM were calculated, respectively. CONCLUSIONS: In the present study, OATP5A1 was deorphanised by characterising amino acids and vitamins as substrates of this transport protein. Estrone-3-sulfate, tyrosine and thiamine were taken up by OATP5A1. Moreover, OATP5A1 mediated the efflux of the amino acids glutamine and glycine, which play essential roles in brain function.
Lactate-activated astrocytes promote NSCLC brain metastasis through extracellular vesicle-mediated miR-8085/TRIM67/ELK1 signaling axis.
Peng H, Tanzhu G, Shi W … +9 more , Xiao G, Zeng Q, Chen L, Wan X, Jing D, Deng H, Marti TM, Fu J, Zhou R
Cell Mol Biol Lett · 2026 May · PMID 42226139 · Full text
Brain metastasis represents an advanced complication in non-small cell lung cancer (NSCLC), characterized by therapeutic resistance and dismal survival outcomes. Although astrocytes are known to influence tumor progressi...
Brain metastasis represents an advanced complication in non-small cell lung cancer (NSCLC), characterized by therapeutic resistance and dismal survival outcomes. Although astrocytes are known to influence tumor progression within the brain microenvironment, their prognostic significance and mechanistic contributions to NSCLC brain metastasis (NSCLC-BM) remain largely unresolved. In this study, we analyze brain metastatic tumors from 66 patients with NSCLC and demonstrate that high infiltration of astrocytes is significantly associated with reduced overall survival. Functional assays reveal that astrocytes enhance the stemness of metastatic tumor cells, a phenotype that is significantly attenuated by silencing astrocytic monocarboxylate transporter 1 (MCT1), thereby blocking lactate uptake. Mechanistically, lactate reprograms astrocytes to release extracellular vesicles enriched in miR-8085, which downregulates the E3 ubiquitin ligase TRIM67 in tumor cells. This suppression stabilizes the transcription factor ELK1 through inhibition of ubiquitin-mediated degradation, promoting stemness maintenance and tumorigenic capacity. Clinically, low TRIM67 and high ELK1 expression correlate with poorer survival in patients with NSCLC-BM. Together, our findings uncover a novel lactate-induced miR-8085/TRIM67/ELK1 signaling cascade that drives brain metastasis progression and highlight potential prognostic biomarkers and therapeutic targets for patients with NSCLC involving the brain.
Exendin-4 averts all-trans-retinal-driven damage to photoreceptors and the retina via the GLP-1R/PKA/CREB1 signaling axis.
He B, Chen Y, Cai P … +6 more , Xi R, Shen X, Guo S, Chen J, Li S, Wu Y
Cell Mol Biol Lett · 2026 May · PMID 42226100 · Full text
BACKGROUND: Atrophic macular degeneration comprises dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1). These disorders lead to irreversible blindness and still lack effective th...
BACKGROUND: Atrophic macular degeneration comprises dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1). These disorders lead to irreversible blindness and still lack effective therapies. The rise of all-trans-retinal (atRAL) brought on by visual cycle disruption closely links to retinal atrophy in both conditions, yet the key downstream targets remain obscure. Exendin-4 (EX-4) is a natural glucagon-like peptide-1 receptor (GLP-1R) agonist. Recent clinical retrospective studies indicate that GLP-1R agonists such as exenatide (synthetic EX-4) can markedly lower the 5-year risk of developing dry AMD. Here, we sought to clarify the protective effect of natural EX-4 against retinal degeneration in atrophic macular degeneration linked to impaired clearance of atRAL. METHODS: Cell and animal paradigms of STGD1 and dry AMD were generated by atRAL-loaded 661W cells and light-exposed Abca4Rdh8 mice, respectively. RNA-sequencing, cell viability assays, morphometric analysis, annexin V/propidium-iodide staining using flow cytometry, quantitative polymerase chain reaction (qPCR), western blotting, immunofluorescence, electroretinography (ERG), fundus photography, hematoxylin and eosin (H&E) histology, and TUNEL staining were integrated to delineate the anti-apoptotic actions of EX-4 and to uncover its underlying protective mechanism. RESULTS: GLP-1R/cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA)/cAMP response element-binding protein 1 (CREB1) signaling was markedly downregulated in atRAL-challenged 661W cells and in neural retina of light-exposed Abca4Rdh8 mice. EX-4 reinstated this pathway, suppressed caspase-3 activation and DNA damage, and curtailed apoptosis in both cell and tissue contexts. Silencing of Glp1r or the PKA catalytic subunits by small interfering RNA (siRNA) abrogated EX-4-induced activation of the PKA/CREB1 axis in atRAL-loaded 661W cells. Pharmacologic blockade of CREB1 phosphorylation with the PKA inhibitor H-89 or the CREB1 inhibitor 666-15 largely nullified the DNA-protective and anti-apoptotic benefits conferred by EX-4 in 661W cells following atRAL exposure, suggesting that the GLP-1R/PKA/CREB1 signaling axis contributes to its cytoprotection action. More importantly, intraperitoneal injection of EX-4 significantly preserved retinal structure and function in Abca4Rdh8 mice after exposure to light, and mitigated punctate lesions in the fundus. CONCLUSIONS: EX-4 exerted anti-apoptotic and DNA-protective effects against atRAL-induced photoreceptor loss and retinal degeneration at least partially through activating the GLP-1R/PKA/CREB1 pathway. These findings suggest that GLP-1R agonists could serve as potential preventive therapeutics for atrophic macular degeneration associated with atRAL toxicity, including dry AMD and STGD1.
OTULIN protects hyperoxia-induced neonatal lung injury and modulates mitochondrial protein OPA1 in association with the E3 ubiquitin ligase RNF31.
Huang L, Liu Q, Zhang A … +7 more , Liu Y, Huang F, Wang J, Tan M, Wang D, Zhao M, Wu X
Cell Mol Biol Lett · 2026 May · PMID 42218396 · Full text
The deubiquitinating enzyme OTULIN has been implicated in the development of lung injury, and regulating its expression may either exacerbate or alleviate pulmonary inflammatory damage. In this study, we aimed to investi...
The deubiquitinating enzyme OTULIN has been implicated in the development of lung injury, and regulating its expression may either exacerbate or alleviate pulmonary inflammatory damage. In this study, we aimed to investigate the role of deubiquitinating enzyme OTULIN in hyperoxia-induced lung injury and the underlying mechanisms involved. A bronchopulmonary dysplasia (BPD) model was established by exposing neonatal mice to a hyperoxic environment, and the effects of regulating OTULIN expression on mitochondrial homeostasis in pulmonary epithelial cells were further examined under hyperoxic conditions. In addition, we investigated the mechanisms through which OTULIN regulates mitochondrial-associated proteins and the ubiquitination mechanisms of differential mitochondrial protein OPA1. The results showed that hyperoxia induced significant lung injury in neonatal mice and was accompanied by upregulation of OTULIN expression. Additionally, hyperoxia disrupted mitochondrial homeostasis in neonatal mice lung tissue, as observed by a reduction in mitochondrial number and increased mitochondrial fusion and autophagy. After hyperoxia exposure, overexpression of OTULIN significantly reduced mitochondrial reactive oxygen species (ROS) levels in alveolar epithelial cells, maintained mitochondrial membrane potential, and promoted mitochondrial homeostasis. Mechanistically, OTULIN was found to directly interact with OPA1 and regulate its ubiquitination status. The E3 ubiquitin ligase RNF31 was identified as a key regulator of OPA1 stability, with knockdown of RNF31 reducing OPA1 levels. Moreover, OTULIN regulated the expression of both OPA1 and RNF31 and affected the stability of OPA1 and mitochondrial function through RNF31-dependent mechanisms. In vivo experiments further showed that knockdown of OTULIN aggravated hyperoxia-induced lung injury in neonatal mice, characterized by alveolar simplification, increased fibrosis, and further impairment of mitochondrial function, whereas overexpression of OTULIN alleviated these pathological changes. In conclusion, deubiquitinating enzyme OTULIN protected hyperoxia-induced neonatal lung injury and modulates mitochondrial protein OPA1 in association with the E3 ubiquitin ligase RNF31. These findings provide new insights into the pathogenesis of BPD and highlight the therapeutic potential of targeting the OTULIN/RNF31-OPA1 axis.
KAP1 SUMOylates and stabilizes SR-A to facilitate glycated LDL transcytosis and accelerate atherosclerosis.
Shu M, Cheng W, Yu F … +6 more , Zhang L, Wang L, Shu Y, Wang R, Xue B, Jin S
Cell Mol Biol Lett · 2026 May · PMID 42218384 · Full text
BACKGROUND: Atherosclerosis (AS)-associated cardiovascular disease is the main cause of global mortality. The excessive retention of glycated low-density lipoprotein (G-LDL) under the vascular endothelium promotes AS. In...
BACKGROUND: Atherosclerosis (AS)-associated cardiovascular disease is the main cause of global mortality. The excessive retention of glycated low-density lipoprotein (G-LDL) under the vascular endothelium promotes AS. In addition, G-LDL supports a role in promoting the expression of scavenger receptor A (SR-A), increasing SR-A-mediated transcytosis of G-LDL in endothelial cells (ECs), consequently accelerating the progression of atherosclerosis. However, the underlying mechanism used by G-LDL to promote SR-A expression has not been elucidated, thus representing the aim of this work. METHODS: The protein-protein interaction of the E3 SUMO ligase KRAB structural domain-associated protein 1 (KAP1) and SR-A were confirmed by co-immunoprecipitation (co-IP)-based immunoblotting and immunofluorescence in human umbilical vein endothelial cells (HUVECs). G-LDL uptake and transcytosis in KAP1-silencing or overexpressing HUVECs were assessed. The effect of KAP1 on de-ubiquitination and SUMOylation of SR-A was determined by co-IP-based immunoblotting. The role of KAP1 on G-LDL-induced atherosclerosis was tested by adenovirus-mediated knockdown in ApoE mice. RESULTS: KAP1 was identified as an enhancer of SR-A, promoting its expression. KAP1 bound to SR-A and promoted SUMO1 modification of the SR-A lysine (K)22, which hampers K48-linked ubiquitination and proteasomal degradation of SR-A. KAP1 deficiency attenuated G-LDL-induced SR-A activation both in vitro and in vivo, reduced aortic G-LDL retention, and consequently, atherosclerotic vulnerable plaque formation in murine models. CONCLUSIONS: This study identifies a SUMOylation-ubiquitination crosstalk that governs SR-A stability, revealing KAP1 as a key molecular switch controlling SR-A turnover in endothelial cells. These findings provide a mechanistic basis for how G-LDL accelerates atherosclerosis.
AARS1 promotes diabetic kidney disease through rewiring Akt and NF-κB signaling to suppress autophagy and sustain inflammation.
Tian L, Wang Y, Guan C … +4 more , Agborbesong E, Zhou JX, Mou S, Li X
Cell Mol Biol Lett · 2026 May · PMID 42215867 · Full text
BACKGROUND: Diabetic kidney disease (DKD) is characterized by metabolic reprogramming, autophagy impairment, and chronic inflammation, but the molecular mechanisms linking these processes are not fully understood. Lactyl...
BACKGROUND: Diabetic kidney disease (DKD) is characterized by metabolic reprogramming, autophagy impairment, and chronic inflammation, but the molecular mechanisms linking these processes are not fully understood. Lactylation has emerged as an important metabolic-epigenetic regulatory mechanism in diabetic tissues. Alanyl-tRNA synthetase 1 (AARS1) has recently been identified as a lactyltransferase, but whether and how AARS1-mediated lactylation contributes to tubular stress responses and DKD progression remains unclear. METHODS: Kidney-specific Aars1 knockout mice and β-alanine treatment were used in streptozotocin-induced and db/db diabetic mouse models. Human proximal tubular epithelial cells cultured under high-glucose conditions, including CRISPR/Cas9-mediated AARS1 knockout cells, were used for mechanistic studies. AARS1-dependent transcriptional programs were analyzed by CUT and Tag, ChIP assays, and luciferase reporter assays. RESULTS: AARS1 was upregulated in diabetic kidneys and directly lactylated Akt and the NF-κB subunit p65, enhancing their phosphorylation and activation. This modification promoted autophagy impairment, inflammatory cytokine expression, tubular injury, and macrophage accumulation. CUT and Tag analysis further revealed AARS1-dependent transcriptional control of HK2, PFKP, ZEB1, and PPP6C, linking AARS1 to glycolytic reprogramming and fibrotic signaling. Mechanistically, AARS1 operated within a glycolysis-lactate-NF-κB feedback circuit, in which glycolysis-driven lactate increased the lactylation and activation of NF-κB, promoting AARS1 transcription and reinforcing glycolytic reprogramming and chronic tubular stress. Genetic deletion of Aars1 or pharmacological inhibition with β-alanine reduced protein lactylation, restored autophagy, attenuated inflammation, and significantly slowed DKD progression in both diabetic mouse models. CONCLUSIONS: These findings identify AARS1 as a metabolic-epigenetic amplifier that rewires Akt- and NF-κB-dependent signaling to sustain chronic tubular stress and fibrotic remodeling in DKD, highlighting the AARS1-lactylation axis as a potential therapeutic target.
KRAS mutations are associated with nCRT resistance via enhanced DNA double-strand break repair and support a deep learning prediction framework in LARC.
Liu H, Bu D, Yu G … +8 more , Wei R, Jin H, Liu Y, Guan X, Zhao Z, Chen H, Zhao Y, Jiang Z
Cell Mol Biol Lett · 2026 May · PMID 42210090 · Full text
BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer (LARC), yet clinically validated biomarkers for predicting response remain lacking. This study aimed to identi...
BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer (LARC), yet clinically validated biomarkers for predicting response remain lacking. This study aimed to identify candidate molecular events associated with nCRT response and to develop a pretreatment prediction framework integrating genomic and pathological information. METHODS: Whole-exome sequencing (WES) was performed on pretreatment tumors from 67 patients with LARC, and an additional 22 published WES cases were integrated to compare genomic differences between responders (R) and nonresponders (NR). Using histopathological whole-slide images (WSIs; n = 106) and genome-derived features, a weakly supervised, multimodal deep learning fusion model was developed to predict nCRT response. Multiomics profiling was used for exploratory pathway characterization, and functional assays were conducted in colorectal cancer cell lines and mouse models harboring KRAS or KRAS. RESULTS: WES identified 41 response-associated hotspot codon events. KRAS and KRAS were detected in the NR group in this cohort and were directionally aligned with poor response, indicating an association with nCRT resistance. Because these events are low-frequency alterations, and the study is a single-center retrospective cohort with limited numbers of carriers, multivariable adjustment for key covariates (including stage and T/N status) was not feasible; thus, these findings should be interpreted as exploratory candidate signals. The multimodal fusion model showed good discrimination within the cohort (AUC = 0.882). Mechanistically, exploratory multiomics analyses and orthogonal functional assays were consistent with KRAS variants being associated with altered DNA damage repair signaling and increased repair capacity, with the functional assays providing the main support for this interpretation. CONCLUSIONS: The proposed genome-pathology fusion model provides a research-oriented framework for pretreatment prediction and risk stratification of nCRT response in LARC. KRAS and KRAS are presented as candidate molecular events aligned with poor response, but their independent predictive value and the clinical usability of the model require validation in larger, multicenter prospective cohorts that include external WSI data, together with systematic evaluation of thresholding and calibration before clinical translation.
Multi-omic screening identifies RBMXL3 as a primate-specific RNA-binding protein and candidate regulator of RNA metabolism in human spermatogenesis.
Barszcz AJ, Tutak K, Zyprych-Walczak J … +14 more , Dassi E, Ilaslan E, Dąbrowska M, Malcher A, Olszewska M, Cysewski D, Nadel A, Kolanowski T, Madeja ZE, Hrab M, Yatsenko AN, Kurpisz M, Warkocki Z, Rozwadowska N
Cell Mol Biol Lett · 2026 May · PMID 42204675 · Full text
BACKGROUND: RBMXL3 is a primate-specific gene localized on the X chromosome, of which the expression is detectable mainly in the male gonad. So far, very little is known about the RBMXL3 protein function and its molecula...
BACKGROUND: RBMXL3 is a primate-specific gene localized on the X chromosome, of which the expression is detectable mainly in the male gonad. So far, very little is known about the RBMXL3 protein function and its molecular interactions. However, recent reports mention the RBMXL3 gene in the context of human spermatogenesis, cancer, and a breathing disorder that affects newborns. In this study, we investigate the RBMXL3's molecular network on a genome-wide scale using the human seminoma cell line (TCam-2) as a male germline in vitro model. METHODS: By using transcriptomic (RNA sequencing [RNA-seq] and enhanced crosslinking and immunoprecipitation [eCLIP]) and proteomic (co-immunoprecipitation coupled with mass spectrometry, (Co-IP-MS)) approaches, we show RBMXL3's importance in RNA metabolism. In addition, western blot, quantitative polymerase chain reaction with reverse transcription (qRT-PCR), immunostaining, and confocal imaging were used to investigate the function of RBMXL3. Finally, we used a plasmid-based L1 retrotransposition assay to demonstrate the suppressive effect of RBMXL3 on human Long Interspersed Nuclear Element-1 (LINE-1, L1) retrotransposition. RESULTS: Our RNA-seq data show that RBMXL3 expression drives gene expression changes and influence alternative splicing in human cells. Moreover, by performing eCLIP, we provide proof that RBMXL3 binds to a wide range of RNA transcripts. In addition, we confirmed the nuclear localization of RBMXL3 in TCam-2 cells and its presence in spermatogonia and spermatocytes within the human testis. Finally, we report for the first time that RBMXL3 restricts human LINE-1 retrotransposition. CONCLUSIONS: Our findings for the first time identify primate-specific RBMXL3 protein as a new upstream regulator of RNA metabolism, characterized by broad RNA-binding activity in human TCam-2 cells. Finally, we show that RBMXL3 expression heavily reduces LINE-1 retrotransposition in human cells, underlying RBMXL3 importance in maintaining genome integrity. Our data suggest that RBMXL3 may contribute to the regulation of transcriptome dynamics in male germ cells, while its broader functional implications remain to be determined.
Enolase 2-mediated lactylation-dependent disruption of the GNL3-MDM2-p53 axis in age-related osteoarthritis.
Hua F, Nan J, Wu R … +7 more , Zhang B, Liu Q, Ma T, Zhang Z, Hu Y, Xie J, Yang Y
Cell Mol Biol Lett · 2026 May · PMID 42192505 · Full text
BACKGROUND: Age-related osteoarthritis (OA) involves metabolic dysregulation and chondrocyte senescence. This study examined the nonmetabolic role of enolase 2 (ENO2) in OA pathogenesis and its therapeutic potential. MET...
BACKGROUND: Age-related osteoarthritis (OA) involves metabolic dysregulation and chondrocyte senescence. This study examined the nonmetabolic role of enolase 2 (ENO2) in OA pathogenesis and its therapeutic potential. METHODS: Human aged and OA cartilage (n = 3 per group) underwent F-FDG positron emission tomography (PET)-computed tomography (CT) imaging, proteomic profiling, and immunohistochemistry. In vitro chondrocyte senescence models were generated by inducing doxorubicin-induced stress and serial passaging. Protein-protein interactions (ENO2-GNL3-MDM2) were validated by co-immunoprecipitation (IP), GST pull-down, and site-directed mutagenesis (E4A-ENO2 and K5R-GNL3 mutants). Lactylation was assessed using lactylomics and immunoprecipitation. The therapeutic effect of the ENO2-specific inhibitor POMHEX was evaluated in C57BL/6 J mice (n = 6 per group) via intra-articular injection for 16 weeks. Outcomes included histology, micro-CT, pain behavior, and gait analysis. RESULTS: Proteomics revealed ENO2 upregulation in aged human cartilage. In vitro, ENO2 overexpression promoted extracellular matrix catabolism, senescence, and glycolysis, whereas ENO2 knockdown attenuated these processes. Mediated by its Glu-4 residue, nuclear ENO2 bound GNL3 lactylated at Lys-5. This interaction displaced MDM2 from GNL3, resulting in MDM2 destabilization, impaired ubiquitination, p53 accumulation, and persistent senescence. Moreover, p53 transcriptionally activated ENO2, establishing a pathological positive feedback loop. Pharmacological inhibition of ENO2 with POMHEX disrupted ENO2-GNL3 binding, restored p53 degradation, reduced senescence markers in vitro, and mitigated cartilage degradation, subchondral bone sclerosis, and pain in aged mice. CONCLUSIONS: ENO2 promotes OA progression through a lactate-dependent, lactylation-mediated disruption of the GNL3-MDM2-p53 axis, leading to a senescent feedback loop. Targeting ENO2 may represent a novel disease-modifying therapeutic approach for age-related OA.
HucMSC-mediated stromal metabolic reprogramming in reactivating aged ovaries: a single-cell transcriptomic perspective.
Zhang YY, Mei Y, Yang W … +12 more , Zhou H, Zhou Y, Chen Y, Zhang Y, Chen J, Jin J, Tong X, Shi L, Huang D, Guo G, Zhang YL, Zhang S
Cell Mol Biol Lett · 2026 May · PMID 42192288 · Full text
BACKGROUND: Aging-induced decline in ovarian function and oocyte quality contributes to female infertility. However, the mechanisms underlying human umbilical cord-derived mesenchymal stem cell (HucMSC)-mediated rejuvena...
BACKGROUND: Aging-induced decline in ovarian function and oocyte quality contributes to female infertility. However, the mechanisms underlying human umbilical cord-derived mesenchymal stem cell (HucMSC)-mediated rejuvenation of aged ovaries remain poorly understood. This study aimed to systematically investigate whether and how HucMSCs restore ovarian function and oocyte quality and elucidate the potential pathways involved. METHODS: Aged mice received in situ ovarian injections of HucMSCs. Ovarian follicular development and fertility outcomes were assessed. Low-input RNA-seq and single-cell RNA sequencing (scRNA-seq) were applied to evaluate transcriptomic heterogeneity in oocytes and somatic cells separately. Additionally, the molecular change and function of HucMSC-primed stromal cells (SCs) in aged ovaries were assessed to validate SCs' functional roles in ovarian microenvironment improvement. RESULTS: HucMSC treatment enhanced follicular development, increased antral follicle numbers, and partially restored fertility in aged mice. Oocyte transcriptomes in HucMSC-treated mice resembled those of young mice, with 75% of aging-dysregulated genes (notably mitochondrial respiratory chain complex assembly-related genes) reverting to youthful expression patterns. scRNA-seq revealed upregulated transcription and glycolysis in granulosa cells (GCs), alongside stromal cell fate redirection toward steroidogenesis and folliculogenesis instead of fibrosis. Transplantation of HucMSC-primed SCs replicated these restorative effects. Mechanistically, HucMSCs promoted pregnenolone synthesis in stromal cells, facilitating follicular development. CONCLUSIONS: HucMSCs reactivate aged ovaries by inducing metabolic reprogramming in both oocytes and somatic cells, enhancing mitochondrial function in oocytes, and redirecting stromal cells toward steroidogenic and folliculogenic pathways. These findings underscore stromal cell functional modulation as a critical mechanism in counteracting ovarian aging and revealing the potential of stromal cells as therapeutic targets.
GPR161 contributes to macrophage glycolytic reprogramming via targeting C5aR1 in acute lung injury.
Li YH, Yang X, Chen Y … +14 more , Wang M, Shu H, Wan K, Sun DT, Yao N, Yang YL, Zhao F, Han BB, Yao C, Song B, Bao J, Sun GY, Li J, Li XF
Cell Mol Biol Lett · 2026 May · PMID 42185764 · Full text
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are severe respiratory disorders characterized by a dysregulated and excessive inflammatory response within the pulmonary syst...
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are severe respiratory disorders characterized by a dysregulated and excessive inflammatory response within the pulmonary system. Recent studies have underscored the pivotal role of macrophage activation in driving inflammatory processes, with glycolytic reprogramming emerging as a critical regulator of macrophage function. In this study, we observed significantly elevated expression levels of G protein-coupled receptor 161 (GPR161) in peripheral circulating monocytes from patients with ARDS, with GPR161 expression positively correlating with disease severity. Utilizing genetically engineered mouse models, including global and macrophage-specific conditional knockout mice, we demonstrated that GPR161 deficiency attenuated pulmonary inflammatory damage in lipopolysaccharide-induced and sepsis-associated ALI mice. In vitro experiments further elucidated the essential role of GPR161 in macrophage activation and glycolytic reprogramming. Mechanistic investigations, integrating RNA sequencing with co-immunoprecipitation and surface plasmon resonance assays, identified complement component 5a receptor 1 (C5aR1) as a downstream target of GPR161 and showed that GPR161 promotes glycolytic reprogramming in macrophages by suppressing C5aR1 expression. Collectively, these findings demonstrate that GPR161 enhances macrophage activation and glycolytic reprogramming in ALI/ARDS through a C5aR1-dependent mechanism. These results establish macrophage GPR161 as a promising therapeutic target for the treatment of ALI/ARDS.
Neutrophils blend innate and adaptive immunity in early breast milk.
Gomez-Casado G, Saldaña-García N, Cantarero-Cuenca A … +6 more , Gonzalez-Jimenez A, Paz-López G, Garcia-Hurtado P, Tinahones FJ, González-Mesa E, Ortega-Gomez A
Cell Mol Biol Lett · 2026 May · PMID 42174417 · Full text
BACKGROUND: Breast milk not only is the most optimal source of nutrition for newborns but also provides crucial immune support. While there is extensive evidence highlighting the health benefits of breastfeeding, the sci...
BACKGROUND: Breast milk not only is the most optimal source of nutrition for newborns but also provides crucial immune support. While there is extensive evidence highlighting the health benefits of breastfeeding, the scientific understanding behind many of these advantages remains limited. The immune cell fraction of breast milk has been poorly studied, and characterization of this essential component may be crucial to shed light on the subject. Here, we investigate the population of neutrophils in breast milk to unveil their phenotype and functions. METHODS: Neutrophils in human breast milk were characterized by flow cytometry, and their phenotype was contrasted with that of their circulating counterparts using a paired approach. Transmission electron microscopy (TEM), intracellular granule immunocytochemistry, and Giemsa staining were employed to reveal their intracellular structure. In vitro neutrophil incubations were performed to assess the phenotypic modifications of circulating neutrophils in a breast milk environment. Functional assays were carried out to assess the activity of neutrophils and their potential impact on adaptive immunity. Finally, a proteomic approach was used on isolated neutrophils and their supernatant after cultivation to define the protein-based mechanisms involved in their biology. Paired t-tests and one- and two-way analysis of variance (ANOVA) were used for statistical analyses. RESULTS: In the breast milk from the first 5 days (known as colostrum), neutrophils represent most of the cellular compartment. Colostrum neutrophils present a cell surface signature markedly different from circulating neutrophils with a clear CXCR4CD62LCXCR2 phenotype and important differences in other markers. These differences are partially phenocopied upon incubation of blood neutrophils with colostrum whey, implying that cell transition occurs owing to the niche environment. Additionally, colostrum neutrophils exhibit reduced cytoplasmic granule content and altered canonical functions. Proteomic analyses reveal that the most important processes in colostrum neutrophils are related to antigen binding and humoral response pathways. CONCLUSIONS: This study provides evidence of a unique population of neutrophils in early breast milk connected to adaptive immunity, which may hold the key to understanding the mechanisms behind the immunological benefits of breastfeeding.
mA-modificated Linc00707 promotes the progression of TNBC via U2AF2-mediated alternative splicing of ATG4B.
Li H, Li Y, Liu Q … +3 more , Yin C, Zhang Y, Gao P
Cell Mol Biol Lett · 2026 May · PMID 42151774 · Full text
BACKGROUND: Triple-negative breast cancer (TNBC) represents a clinically aggressive breast cancer subtype with limited therapeutic options. Emerging evidence suggests that long intergenic noncoding RNA 00707 (Linc00707)...
BACKGROUND: Triple-negative breast cancer (TNBC) represents a clinically aggressive breast cancer subtype with limited therapeutic options. Emerging evidence suggests that long intergenic noncoding RNA 00707 (Linc00707) plays a role in TNBC; however, the upstream regulators governing Linc00707 expression and the mechanisms by which it contributes to tumor progression remain largely undefined. METHOD: The FOXP3-mediated transcriptional regulation of Linc00707 was analyzed using chromatin immunoprecipitation and luciferase reporter assays. The post-transcriptional regulation of Linc00707 was examined by RNA immunoprecipitation (RIP), methylated RIP, and RNA pull-down assays to assess WTAP-dependent mA modification, IGF2BP2-mediated stabilization, and U2AF2 interaction. RNA sequencing and biochemical analyses were used to identify downstream regulatory pathways. The binding of oligo-anti-Linc00707 to Linc00707 and its ability to disrupt U2AF2 association were confirmed by RIP and RNA fluorescence in situ hybridization (RNA-FISH). Cellular assays and nude mouse xenograft models were employed to evaluate functional and therapeutic effects. RESULTS: FOXP3 was found to transcriptionally activate Linc00707 through direct promoter binding. The WTAP-mediated mA modification enhanced the IGF2BP2-dependent stabilization of Linc00707. In the nucleus, Linc00707 interacted with the splicing factor U2AF2, with nucleotides 1-593 identified as a critical interaction region. Building on this observation, we further showed that the Linc00707-U2AF2 interaction functionally controls U2AF2 expression and stability via FOXP3. The Linc00707-U2AF2 complex was associated with altered alternative splicing of the autophagy-related gene ATG4B, contributing to enhanced TNBC cell proliferation, invasion, and autophagy suppression. Importantly, oligonucleotides complementary to the U2AF2-binding region of Linc00707 (oligo-anti-Linc00707) disrupted this interaction, attenuated Linc00707-driven oncogenic phenotypes, and restored autophagic activity. In vivo, oligo-anti-Linc00707 treatment significantly reduced tumor growth, supporting its therapeutic potential in TNBC. CONCLUSIONS: FOXP3 activates Linc00707 transcription in TNBC. WTAP-mediated mA modification enhances Linc00707 stability via IGF2BP2. Linc00707 recruits U2AF2 to drive oncogenic ATG4B splicing, promoting tumor progression. Oligo-anti-Linc00707 specifically blocks Linc00707-U2AF2 complex formation, reversing its tumor-promoting and autophagy-suppressing functions. Thus, targeting Linc00707 represents a promising therapeutic strategy for TNBC.
Genomic context of mutations in MIR142 in blood cancers: summary and integrative analysis.
Wegorek W, Tire A, Kuznicki D … +5 more , Richter J, Giefing M, Klapper W, Kozlowski P, Galka-Marciniak P
Cell Mol Biol Lett · 2026 May · PMID 42151759 · Full text
MIR142 is the most frequently mutated microRNA (miRNA) gene in cancer, with recurrent alterations observed particularly in hematologic malignancies of lymphoid origin. It is expressed at very high levels in blood cells a...
MIR142 is the most frequently mutated microRNA (miRNA) gene in cancer, with recurrent alterations observed particularly in hematologic malignancies of lymphoid origin. It is expressed at very high levels in blood cells and plays an essential role in the development, differentiation, and maturation of various lymphopoietic and hematopoietic lineages. To gain a deeper understanding of MIR142 mutations, we summarize all data on these mutations, including their frequency in different cancers, their location within the miR-142 precursor, and their functional consequences. We also analyzed MIR142 mutations within a broader genomic context in thousands of cancers, including hundreds of blood neoplasms. Our results show that the most prevalent mutations in the MIR142 gene originate from a clearly distinct hotspot in hematologic malignancies, concentrated mainly within the sequence of the secondary miR-142 precursor. We found substantial differences in mutation frequency and distribution across cancer types. This indicates that MIR142 alterations are not random consequences of an increased mutational load but are likely subject to positive selection, underscoring their biological and clinical significance.
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