Cell. Mol. Biol. Lett. [JOURNAL]
Sun
200 papers
Optimized genetic tracers for viral mediated neuronal projection mapping.
Dulin JN, Ye L, Grider T … +9 more , Rizzo A, Rosenzweig ES, Weber J, Ramakrishnan C, Hsueh B, Deisseroth K, Tuszynski MH, Gibbs D, Poplawski GHD
Cell Mol Biol Lett · 2026 Mar · PMID 41794669 · Full text
Mapping fine axonal projections with high sensitivity remains a major challenge in neuroanatomy. Here, we developed Codon Optimized Membrane Embedded Tracers (COMET), a family of genetically encoded, membrane-anchored fl...
Mapping fine axonal projections with high sensitivity remains a major challenge in neuroanatomy. Here, we developed Codon Optimized Membrane Embedded Tracers (COMET), a family of genetically encoded, membrane-anchored fluorescent proteins optimized for adeno-associated virus (AAV) delivery. COMET tracers—based on codon-optimized SuperFolder GFP (gCOMET) and TdTomato (rCOMET) fused to an H-RAS CaaX prenylation motif—enable robust plasma membrane targeting and enhance fluorescent signal localization to fine-caliber axons. In vivo, COMET tracers significantly outperformed conventional soluble fluorophores and chemical tracers in detecting corticospinal tract (CST) projections, revealing previously underappreciated collateralization and fine arborizations. Following spinal cord injury, COMET provided superior sensitivity for detecting regenerating and sprouting axons compared with biotinylated dextran amine (BDA). Importantly, COMET tracers retained bright native fluorescence after tissue clearing by CLARITY, enabling volumetric imaging of long-range projections without antibody amplification. COMET expands the available toolkit for high-resolution connectomics and regeneration studies, offering a versatile platform for sensitive, scalable, and cell-type-specific neuronal tracing in intact and injured mammalian nervous systems.
The spatiotemporal dynamics of MAMs: mechanisms, pathologies, and therapeutic rewiring.
Xu D, Huang Y, Zhang X … +4 more , Liu B, Wang M, Li Y, Peng Z
Cell Mol Biol Lett · 2026 Mar · PMID 41794668 · Full text
Mitochondria-associated endoplasmic reticulum membranes (MAMs) constitute highly dynamic signaling hubs that coordinate a spatiotemporal network regulating calcium flux, lipid trafficking, and innate immune activation. B...
Mitochondria-associated endoplasmic reticulum membranes (MAMs) constitute highly dynamic signaling hubs that coordinate a spatiotemporal network regulating calcium flux, lipid trafficking, and innate immune activation. Beyond functioning as physical organelle tethers, the plasticity of MAMs is essential for cellular resilience. Notably, maladaptive remodeling of these contacts, which presents a spatiotemporal paradox in that both pathological tightening and excessive dissociation can precipitate dysfunction, underlies the pathogenesis of diverse complex diseases, including neurodegeneration, cardiovascular failure, and kidney injury. In this review, we provide an integrated synthesis of the molecular architecture of MAMs and highlight the indispensable role of endoplasmic reticulum (ER)–mitochondria coupling in sustaining physiological homeostasis. We further dissect how MAM dysregulation operates as a central convergence point for metabolic stress and inflammatory signaling. Additionally, we summarize technological advances such as super-resolution imaging and multi-omics frameworks that increasingly resolve the structural and functional heterogeneity of MAMs. Importantly, emerging evidence indicates a therapeutic paradigm shift: several widely used clinical agents, including sodium-glucose cotransporter 2 (SGLT2) inhibitors and metformin, appear to exert their renoprotective and metabolic benefits by restoring or stabilizing MAM integrity. Together, these insights reposition MAMs not as passive structural bystanders but as actionable, high-value therapeutic targets for next-generation precision medicine and drug repurposing strategies.
High-fat diet leads to male reproductive dysfunction by disrupting lipid-droplet-mediated organelle crosstalk.
Sun L, Wang A, Zhang Y … +7 more , Chen J, Huang P, Zeng K, Huang S, Huang J, Luo J, Wang J
Cell Mol Biol Lett · 2026 Mar · PMID 41792600 · Full text
BACKGROUND: The incidence of reproductive system disorders has been steadily rising in recent years. Moreover, with the rising standard of living, the incidence of metabolic diseases also has been gradually increasing. H...
BACKGROUND: The incidence of reproductive system disorders has been steadily rising in recent years. Moreover, with the rising standard of living, the incidence of metabolic diseases also has been gradually increasing. However, the connection and mechanisms linking reproductive and metabolic diseases are poorly defined. METHODS: For organelle connectivity analysis, we analyzed mitochondria–endoplasmic reticulum (ER) contacts (MERCs) gene expression using a published single-cell RNA sequencing data. The link between lipid droplets (LDs) and actin cytoskeleton was analyzed by mass-spectrometry-based proteomics. By flow-cytometry-based cell sorting coupled with transmission electron microscopy, we explored the LD-mediated mitochondria–endoplasmic reticulum contacts. RESULTS: We found decreased expression of numerous MERC-associated genes, along with a reduction in Leydig cells (LCs), in high-fat diet (HFD) mice. Mechanistically, LDs downregulated the expression of G-actin, leading to the separation of mitochondria from the ER. From a functional perspective, Firsocostat, a lipogenesis enzyme acetyl-CoA carboxylase (ACC) inhibitor, inhibited LD synthesis, which shortened the distance between mitochondria and the ER, improved their functions, and promoted testosterone synthesis. Finally, targeting the LDs offered a promising therapeutic strategy to improve LC function under high-fat conditions, thereby protecting testicular endocrine function. CONCLUSIONS: HFD leads to reproductive dysfunction by disrupting lipid-droplet-mediated Mito–ER contacts.
Correction: A frog peptide provides new strategies for the intervention against skin wound healing.
Li C, Fu Z, Jin T … +13 more , Liu Y, Liu N, Yin S, Wang Z, Huang Y, Wang Y, Zhang Y, Li J, Wu Y, He L, Tang J, Wang Y, Yang X
Cell Mol Biol Lett · 2026 Mar · PMID 41776393 · Full text
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Toll-like receptor 2 drives liver senescence and fibrosis in aging through gut-derived microbial signaling.
Brandt A, Staltner R, Baumann A … +8 more , Burger K, Jelleschitz J, Prada PO, Höhn A, Kopp F, Mayneris-Perxachs J, Fernández-Real JM, Bergheim I
Cell Mol Biol Lett · 2026 Mar · PMID 41772418 · Full text
BACKGROUND: While the role of endotoxins from Gram-negative bacteria has been studied extensively, the contribution of Gram-positive bacterial components—particularly those activating toll-like receptor 2 (TLR2), such as...
BACKGROUND: While the role of endotoxins from Gram-negative bacteria has been studied extensively, the contribution of Gram-positive bacterial components—particularly those activating toll-like receptor 2 (TLR2), such as lipoteichoic acid (LTA)—to liver aging, inflammation, and fibrosis remains poorly understood. Here, we investigated the role of TLR2 and its ligand LTA in liver aging by using murine models, in vitro experiments, and human samples from young and elderly individuals. METHODS: TLR2 ligands were evaluated in serum samples from young (aged 21–33 years) and elderly (aged 65–77 years) healthy individuals. Markers of liver damage, senescence, and inflammation were assessed in 4- and 20-month-old male C57BL/6 and TLR2 knockout (TLR2−/−) mice. In addition, 17-month-old male C57BL/6 mice were treated either with the TLR2 inhibitor ortho-vanillin (60 mg/kg BW in drinking water) or plain water for 4 months and markers as determined above were assessed. The presence of markers of senescence was measured in J774A.1 cells and human peripheral blood mononuclear cells stimulated with LTA. RESULTS: In humans and mice, aging was associated with significantly elevated circulating levels of TLR2 ligands. In aging mice, this was accompanied by increased hepatic Tlr2 mRNA expression. Strikingly, 20-month-old male TLR2−/− mice exhibited reduced markers of senescence (e.g., plasma plasminogen activator inhibitor-1 and liver p16 expression), inflammation (e.g., hepatic neutrophil infiltration, Il1b mRNA expression), and fibrosis (e.g., α-smooth muscle actin expression, Sirius Red staining), compared with age-matched wild-type controls. Similarly, in aged male C57BL/6 J mice showing first signs of impaired intestinal barrier function i.e., rising peripheral TLR2 ligand levels in plasma, treatment with the TLR2 inhibitor ortho-vanillin for 4 months attenuated the progression of liver aging as indicated by attenuated senescence, liver inflammation, and fibrosis. In vitro, stimulation of J774A.1 macrophages and human peripheral blood mononuclear cells with LTA induced the expression of senescence-associated genes p16 and p21. CONCLUSIONS: Collectively, these findings suggest that increased translocation of TLR2 ligands and subsequent activation of TLR2-dependent pathways play a critical role in age-associated liver degeneration. Targeting TLR2 signaling may therefore represent a promising therapeutic approach to mitigate hepatic aging and associated pathologies.
Pseudouridine synthases upregulate 5'-tRF-Lys to inhibit YPEL3 and drive malignant progression in nasopharyngeal carcinoma.
Ren D, Yang M, Mo Y … +12 more , Yan Q, Shi L, Zhang S, Gong Z, Guo C, Zhou M, Xiang B, Tan M, Li G, Chen P, Xiong W, Zeng Z
Cell Mol Biol Lett · 2026 Feb · PMID 41764447 · Full text
Transfer RNA-derived fragments (tRFs) are a recently discovered class of short noncoding RNAs widely distributed in various tissues and cell types. They are involved in the regulation of gene expression and play importan...
Transfer RNA-derived fragments (tRFs) are a recently discovered class of short noncoding RNAs widely distributed in various tissues and cell types. They are involved in the regulation of gene expression and play important roles in both physiological and pathological processes, garnering growing attention. However, the functions and underlying mechanisms of most tRFs in tumorigenesis and progression remain largely unclear. Through small RNA sequencing of nasopharyngeal carcinoma (NPC) and adjacent tissues, we found that among the top 30 highly expressed tRFs in NPC tissues, 13 were derived from lysine tRNAs, forming the 5′-tRF-Lys cluster. This cluster was found to promote NPC cell proliferation, invasion, and migration. Mechanistically, 5′-tRF-Lys binds to the 3′-untranslated region (3′-UTR) of YPEL3 messenger RNA (mRNA), suppressing its expression and thereby activating the Hippo/YAP signaling pathway to drive tumor progression. The elevated expression of pseudouridine synthases PUS1 and PUS7 in NPC tissues catalyzes pseudouridine modification of tRNA-Lys, facilitating its cleavage into 5′-tRF-Lys and accounting for its upregulation. Notably, the PUS1-targeting small-molecule inhibitor mogroside IV-e effectively reversed malignant phenotypes in both in vitro and in vivo NPC models. This study uncovers a novel mechanism in which pseudouridine synthases PUS1 and PUS7 drive the biogenesis of the tRF-Lys cluster, promoting NPC malignancy by suppressing YPEL3 and activating the Hippo/YAP signaling pathway. These findings highlight the therapeutic potential of targeting pseudouridine synthases to reduce tRF-Lys production as a novel strategy for NPC treatment.
PDIA6 promotes the cell proliferation of ESCC by enhancing the disulfide bond formation in TRAF4.
Chen Y, Zhang W, Chen Y … +14 more , Li X, Shi Y, Yuan Q, Han R, Zhang Y, Zhao X, Hu Y, Zhang C, Dong Z, Lee MH, Kim MO, Dong Z, Jiang Y, Liu K
Cell Mol Biol Lett · 2026 Feb · PMID 41761079 · Full text
BACKGROUND: Protein disulfide isomerase A6 (PDIA6), a member of the PDI family, catalyzes disulfide bond formation and assists protein folding. However, its function in esophageal squamous cell carcinoma (ESCC) remains l...
BACKGROUND: Protein disulfide isomerase A6 (PDIA6), a member of the PDI family, catalyzes disulfide bond formation and assists protein folding. However, its function in esophageal squamous cell carcinoma (ESCC) remains largely unknown. METHODS: Functional experiments, including CRISPR/Cas9 knockout, overexpression, rescue assays, and patient-derived xenograft (PDX) models, were performed to evaluate the role of PDIA6 in ESCC proliferation and tumor growth. Pull down-mass spectrometry assays, co-immunoprecipitation, and protein-protein docking assays were used to investigate PDIA6–tumor necrosis factor receptor-associated factor 4 (TRAF4) interactions and disulfide bond formation. Ubiquitination and cycloheximide chase assays were applied to assess the stability of TRAF4. Antisense oligonucleotides (ASOs) targeting PDIA6 were tested for therapeutic efficacy in vitro and in vivo. RESULTS: We found PDIA6 was markedly upregulated in ESCC tissues, with a positive correlation to a poor prognosis. Functional assays demonstrated that PDIA6 significantly promoted the proliferation of ESCC cells both in vitro and in vivo. A pull down–mass spectrometry assay identified TRAF4 as a direct binding partner of PDIA6. Protein-protein docking revealed that PDIA6 interacted with the N-terminal (1-277) domain of TRAF4, enhancing disulfide bond formation at Cys39/Cys42 and Cys83/Cys106. These bonds were indispensable for TRAF4’s E3 ubiquitin ligase activity in facilitating the ubiquitination of AKT. PDIA6 further stabilized TRAF4 by competing with SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1), thereby preventing TRAF4 ubiquitination and proteasomal degradation. The absence of PDIA6 led to the destabilization of TRAF4, resulting in the inactivation of the AKT/mTOR pathway. Rescue experiments using TRAF4 C42A or C83A mutants failed to restore AKT signaling or tumor growth. Notably, ASOs targeting PDIA6 suppressed ESCC growth in vitro and in patient-derived xenografts. CONCLUSIONS: PDIA6 drives ESCC progression by stabilizing TRAF4 and sustaining AKT/mTOR signaling. Targeting PDIA6 with ASOs offers a promising therapeutic strategy for ESCC.
METTL3-mA-STAT1/NF-κB axis: a key switch for the immunosuppressive capacity of mesenchymal stem cells.
Tang K, Han H, Sun R … +4 more , Xu Y, Zhang S, Lai C, Peng Y
Cell Mol Biol Lett · 2026 Feb · PMID 41761052 · Full text
BACKGROUND: Owing to their immunosuppressive nature, mesenchymal stem cells (MSCs)—a type of multipotent stem cell—hold considerable promise for therapeutic applications. Functioning as the primary catalytic subunit of t...
BACKGROUND: Owing to their immunosuppressive nature, mesenchymal stem cells (MSCs)—a type of multipotent stem cell—hold considerable promise for therapeutic applications. Functioning as the primary catalytic subunit of the RNA N6-methyladenosine (m6A) methyltransferase complex, methyltransferase-like 3 (METTL3) plays extensive roles in numerous biological processes. It is hypothesized that METTL3 participates in governing the immunomodulatory functions inherent to MSCs. However, the exact mechanisms governing METTL3’s control over MSCs’ immunosuppressive capacity are poorly defined. METHODS: MSCs extracted from bone marrow were transfected with lentivirus to knockdown or overexpress METTL3, while METTL3 enzyme activity was inhibited using the METTL3 inhibitor STM2457. In vitro co-culture assays and in vivo tumor models revealed that knocking down METTL3 or inhibiting its enzyme activity in MSCs weakened its inhibitory ability on T cells, while overexpressing METTL3 increased its inhibitory ability. in both concanavalin A (ConA)-induced liver injury and dextran sulfate sodium (DSS)-induced colitis models, the therapeutic benefits of MSCs against inflammatory diseases were shown to be dependent on METTL3 RESULTS: Our findings establish METTL3 as a critical regulator of the immunosuppressive capacity of MSCs, mediated through inducible nitric oxide synthase (iNOS) expression. Mechanistic investigations revealed that METTL3 targets JAK1, STAT1, TAB1, and NFKB1 in an IGF2BP1/2-dependent fashion. This regulatory influence stems from METTL3’s ability to potentiate STAT1 and NF-κB signaling pathways. Supporting this, overexpression of METTL3 enhanced NF-κB and STAT1 activation, which consequently elevated iNOS expression. CONCLUSIONS: METTL3 enhances MSC immunosuppression via the m6A–STAT1/NF-κB–iNOS axis, presenting a dual role: it potentiates therapeutic efficacy in inflammatory diseases but exacerbates tumor progression by impairing T-cell infiltration. Targeting METTL3 offers a strategy to optimize MSC-based therapies, though context-specific modulation is essential to balance benefits and risks.
Gene expression regulation by Ca signaling: an updated systematic review.
Zou M, Wang H, Zeng X … +1 more , Zhang X
Cell Mol Biol Lett · 2026 Feb · PMID 41749109 · Full text
All life processes depend on the precise spatiotemporal expression of genes, which involves orderly processes including transcription, posttranscriptional processing, translation, and posttranslational modification. Accu...
All life processes depend on the precise spatiotemporal expression of genes, which involves orderly processes including transcription, posttranscriptional processing, translation, and posttranslational modification. Accumulating evidence demonstrates that Ca is the most critical second messenger that orchestrates nearly all fundamental biological processes vital for maintaining normal physiological functions. Ca homeostasis/signaling is primarily maintained through Ca influx, cytoplasmic Ca release, Ca store cycling, and binding and release of Ca buffers. Their coordinated interactions ensure that Ca concentrations remain within the physiologically appropriate range. Ca signaling must be appropriately activated or suppressed during cellular signal transduction to support specific functions, and its dysregulation can trigger various pathological conditions. This review summarizes recent progress in Ca signaling regulatory networks, including the roles of key regulatory elements/toolkits, the functional significance of Ca signals in different microdomains, and the influence of Ca signaling on gene expression, along with the underlying mechanisms at various stages of gene expression. The involvement of Ca, both independently and collaboratively, in the nucleus, cytoplasm, subcellular microdomains such as mitochondria, and the extracellular space, in the multi-level regulation of gene expression, has been extensively studied. This information is essential for understanding the mechanisms underlying gene expression and for advancing the diagnosis and treatment of diseases. Finally, we propose forward-looking recommendations to address current research gaps, aiming to provide valuable references for researchers in this field.
DNA topological regulation in RNA polymerase II transcription.
Bunch H
Cell Mol Biol Lett · 2026 Feb · PMID 41735852 · Full text
RNA polymerase II (Pol II) is the main enzyme that synthesizes protein-coding messenger RNA and a subset of nonprotein coding RNA molecules based on the DNA sequences harboring genetic information in eukaryotes. Pol II e...
RNA polymerase II (Pol II) is the main enzyme that synthesizes protein-coding messenger RNA and a subset of nonprotein coding RNA molecules based on the DNA sequences harboring genetic information in eukaryotes. Pol II engagement with and dissociation from genes and its catalytic rate and polymerization processivity are modulated by diverse transcriptional elements. These factors control Pol II directly or modulate transcriptional microenvironments, chromatin, and nucleic acid structures. Classical and recent studies have reported multifaceted, important functions of DNA topology and structure and DNA topological regulators including DNA topoisomerases (TOPs), for controlled Pol II transcription. Furthermore, recent studies have indicated intriguing crosstalk among transcriptional factors, TOP2, and DNA damage response/repair factors in transcription, in particular, in the transcriptional initiation and elongation steps. This review updates and discusses these important findings regarding DNA topological modulations and the molecular mechanisms of TOP2 regulation in Pol II transcription.
From hPSCs to MSCs: differentiation strategies, pathways, and the emergence of common regulatory networks.
Liang S, Qian Z, Wang Y … +2 more , Huangfu J, Ren W
Cell Mol Biol Lett · 2026 Feb · PMID 41735837 · Full text
Mesenchymal stem/stromal cells (MSCs) derived from human pluripotent stem cells (hPSCs) represent a scalable and homogeneous source for regenerative medicine. To date, multiple differentiation protocols have been develop...
Mesenchymal stem/stromal cells (MSCs) derived from human pluripotent stem cells (hPSCs) represent a scalable and homogeneous source for regenerative medicine. To date, multiple differentiation protocols have been developed to direct hPSCs toward an MSC fate, with intermediate cell states arising from diverse lineages, including trophoblast, neural crest, mesoderm, and endoderm. Despite these divergent differentiation strategies, the induced MSCs exhibit similar phenotypes and biological functions, suggesting convergent molecular programs underlying MSC specification. In this review, we discuss current strategies for differentiating hPSCs into MSCs and summarize the key signaling pathways, with a focus on the transcriptional regulators that govern these lineage-specific differentiation routes. To identify common regulatory nodes across different lineages, we analyzed publicly available transcriptomic datasets from representative hPSC-to-MSC protocols deposited in the Gene Expression Omnibus (GEO) database. Comparative analysis revealed a core set of consistently dysregulated genes and enriched pathways, particularly those involved in extracellular matrix (ECM)-receptor interaction, focal adhesion, and the PI3K–Akt signaling pathway. Notably, SMAD3, along with AP-1 family members (JUN, JUND, FOSL1, FOSL2) and the associated regulatory targets (FN1 and COL1A1) emerged as recurrent hubs in mesenchymal commitment. These findings highlight both the plasticity and convergence in the induction of MSCs from hPSCs and provide a molecular framework for optimizing differentiation strategies and ensuring product consistency in regenerative applications.
Role of autophagy in antiviral innate immunity.
Xie J, Jiao P, Wang D … +8 more , Shi M, Yuan C, Su L, Zhang G, Wang Y, Ma Z, Li L, Liu W
Cell Mol Biol Lett · 2026 Feb · PMID 41735833 · Full text
Autophagy exerts an important effect on preserving homeostasis of cellular metabolism through degrading superfluous intracellular components. In addition, it serves as the defense mechanism for eliminating invading patho...
Autophagy exerts an important effect on preserving homeostasis of cellular metabolism through degrading superfluous intracellular components. In addition, it serves as the defense mechanism for eliminating invading pathogens, such as viruses, by the host. The onset of a viral infection triggers autophagy, thereby initiating the innate immunity via the pattern recognition receptor pathways. As a result, interferons and other proinflammatory factors are produced. Furthermore, autophagy specifically targets immune components linked to viral particles for degradation. Through presenting virus-derived antigens to T lymphocytes, this process supports adaptive immunity. Nonetheless, certain viruses evolve mechanisms for inhibiting autophagy, enabling evasion of degradation and immune detection, since autophagy is frequently related to inflammatory diseases, including infections, autoimmune disorders, cancer, metabolic syndromes, neurodegenerative conditions, and cardiovascular and liver diseases. This review aims to summarize the current knowledge regarding the key molecules and specific molecular mechanisms that underlie the pattern recognition receptor signaling where autophagy is implicated during viral infections.
Astragaloside IV represses the immune evasion and acidic microenvironment of oral squamous cell carcinoma.
Zhao W, Zheng H, Chang Y … +8 more , Shang T, Wang L, Liu J, Deng J, Pan Z, Hu X, Huang X, Cui Y
Cell Mol Biol Lett · 2026 Feb · PMID 41735828 · Full text
Immune evasion and immunosuppression are important hallmarks of human malignancies. Astragaloside IV (AST) is one of the effective ingredients in Astragalus, which has been confirmed to enhance antitumor immunity. Howeve...
Immune evasion and immunosuppression are important hallmarks of human malignancies. Astragaloside IV (AST) is one of the effective ingredients in Astragalus, which has been confirmed to enhance antitumor immunity. However, the functions and underlying mechanism of AST on oral squamous cell carcinoma (OSCC) tumorigenesis remain undetermined. Our present work tried to test whether and how AST inhibited OSCC immune evasion and ameliorated CD8+ T cell-mediated antitumor response in immune microenvironment. The results of the present work indicated that AST repressed OSCC cells’ proliferation and migration in dosage-dependent manner. In a co-culture system analysis of CD8+ T and OSCC cells, AST enhanced the antitumor activity of CD8+ T cells to impair the OSCC immune evasion. Moreover, AST also repressed the lactate secretion and extracellular acidification. Furthermore, excess lactate accumulation triggered the PD-L1 enrichment on OSCC cells in acidic microenvironment. Mechanistically, AST targeted MCT1 to degrade its mRNA stability, thereby mitigating the extracellular acidification and inhibiting the escape of OSCC from CD8+ T cells’ killing. This study indicates that AST could ameliorate the acidic microenvironment in OSCC to improve CD8+ T cell-mediated antitumor immune response. Our finding might offer novel insights for the anti-tumor effect of AST and provide a potential therapeutic strategy for OSCC.
Gut microbiota-derived trimethylamine N-oxide contributes to cardiomyocyte pyroptosis and cardiac injury via the tRF-Glu-ANT1-GSDMD axis.
Wang T, Ren W, Chen X … +7 more , Wang X, Liu M, Zhang Y, Li Z, Wang Y, Song Z, Diao H
Cell Mol Biol Lett · 2026 Feb · PMID 41735825 · Full text
AIMS: Recent research has shown that the gut microbiota arrests the progression of myocardial infarction (MI) by modulating immune inflammation, oxidative stress, and metabolism. However, the mechanism by which gut-deriv...
AIMS: Recent research has shown that the gut microbiota arrests the progression of myocardial infarction (MI) by modulating immune inflammation, oxidative stress, and metabolism. However, the mechanism by which gut-derived trimethylamine N-oxide (TMAO) promotes cardiomyocyte pyroptosis following MI remains unclear. METHODS AND RESULTS: We found that a high-choline diet exacerbated cardiac injury in mice by disrupting the intestinal barrier. Under high-choline conditions, the expression levels of tRF-1:31-Glu-TTC-2 (tRF-Glu) derived from tRF and tiRNAs (tsRNAs) were elevated, serving as a key target for intervention in cardiomyocyte pyroptosis. Loss of tRF-Glu significantly ameliorated TMAO-induced deterioration of myocardial fibrosis and cardiac function. Mechanistically, tRF-Glu directly binds to the mitochondrial inner membrane protein ANT1 and stabilizes its expression by inhibiting ubiquitination. Cardiomyocyte knockdown of ANT1 significantly blocked the generation of TMAO-induced cardiomyocyte mitochondrial reactive oxygen species, restored cardiomyocyte membrane potential, and reduced mitochondrial DNA (mtDNA) leakage. CONCLUSIONS: Our findings indicate that tRF-Glu inhibits the ubiquitination of ANT1 under the induction of TMAO, which in turn activates gasdermin D (GSDMD) and mtDNA release, accelerating cardiac remodeling. In conclusion, our study provides new insights into the role of the gut microbial metabolite-driven tRF-Glu–ANT1–GSDMD pathway in blocking cardiomyocyte pyroptosis and cardiac injury.
Gut Lachnospiraceae improves white matter injury-related cognitive decline by increasing L-arginine.
Xu Y, Huang L, Sun L … +10 more , Li C, Zhou C, Liu P, Zhang Z, Deng S, Mao C, Hu Z, Bao X, Xia S, Xu Y
Cell Mol Biol Lett · 2026 Feb · PMID 41724956 · Full text
BACKGROUND: White matter injury (WMI) is the most prevalent lesion in cerebral small vessel disease and a major contributor to cognitive decline. Recent studies have highlighted the critical role of gut microbiota in reg...
BACKGROUND: White matter injury (WMI) is the most prevalent lesion in cerebral small vessel disease and a major contributor to cognitive decline. Recent studies have highlighted the critical role of gut microbiota in regulating brain disorders. However, the role of gut microbiota in WMI-related cognitive decline remains unclear. METHODS: A bilateral carotid artery stenosis (BCAS) mouse model was established to mimic WMI and related cognitive decline. Fecal microbiota transplantation was employed to verify the causal relationship between gut microbiota dysbiosis and WMI. 16 S rRNA gene sequencing was used to analyze gut microbiota and its potential functions. Untargeted metabolomics was applied to identify differential metabolites. Cognitive function was assessed through Y-maze, novel object recognition, and fear conditioning tests. WMI was assessed using in vivo imaging, immunostaining, and electron microscopy. The changes in oligodendrocyte lineage cells, microglia, and blood-brain barrier were investigated using immunofluorescence staining, EdU cell proliferation assays, and Western blotting. Patients with ischemic WMI were included to examine the correlation between serum L-arginine (L-Arg) levels, brain imaging, and cognition. RESULTS: We discovered that BCAS mice exhibited gut microbiota dysbiosis and reduced arginine biosynthesis, with decreased L-Arg levels in serum and white matter. Fecal microbiota from BCAS mice resulted in WMI and related cognitive decline in normal mice. Serum L-Arg levels were reduced in patients with ischemic WMI and were closely associated with WMI and cognitive decline. Importantly, L-Arg supplementation improved WMI-related cognitive decline in BCAS mice. Mechanistically, L-Arg promoted oligodendrocyte precursor cell proliferation and differentiation, enhanced the anti-inflammatory activity of microglia, and reduced blood-brain barrier leakage, thereby mitigating WMI-related cognitive decline. Furthermore, Lachnospiraceae was identified as the main source of gut-to-brain L-Arg. Supplementation with Lachnospiraceae alleviates WMI-related cognitive decline. CONCLUSION: Overall, our study revealed the critical role of gut microbiota, particularly Lachnospiraceae, and L-Arg in improving WMI-related cognitive decline, providing novel strategies for understanding and treating WMI-related cognitive decline.
Bannakunin: a dual-target Kunitz inhibitor bridging anticoagulation (FXa/XIIa) and anti-platelet (α2β1/P2Y12) pathways.
He M, He Y, Feng X … +7 more , Li Z, Lin T, Yang J, Luo H, Mu L, Yang H, Wu J
Cell Mol Biol Lett · 2026 Feb · PMID 41724941 · Full text
BACKGROUND: Thrombosis is a major cause of morbidity and mortality worldwide. Consequently, there is an ongoing search for efficacious and safe anti-thrombotic drugs. Haematophagous animals have developed a large variety...
BACKGROUND: Thrombosis is a major cause of morbidity and mortality worldwide. Consequently, there is an ongoing search for efficacious and safe anti-thrombotic drugs. Haematophagous animals have developed a large variety of salivary bioactive components to counteract host haemostatic responses. We aim to discover anti-thrombotic agents with dual anti-platelet and anticoagulant activities. METHODS: A novel single Kunitz domain inhibitor (Bannakunin) precursor cloned from the salivary glands complementary DNA (cDNA) library of blood-sucking black fly Simulium bannaense was expressed in Escherichia coli. Recombinant Bannakunin was purified by Immobilised Metal Affinity Chromatography and High-Performance Liquid Chromatography. The secondary structure was determined by circular dichroism spectroscopy. The anti-thrombotic activity was evaluated through carotid artery thrombosis and tail vein thrombosis models. The inhibitory activity was evaluated using serine protease inhibition assays, SPR and molecular docking. The regulation on platelets was assessed by platelet aggregation, clot retraction and platelet spreading assays. Subsequently, its target receptors and signalling pathways were investigated through western blotting, enzyme-linked immunosorbent assay (ELISA) and flow cytometry. RESULTS: Recombinant Bannakunin demonstrated significant anti-thrombotic efficacy in murine FeCl3-induced carotid artery and carrageenan-induced tail vein thrombosis models and did not induce bleeding complications. Simultaneously, Bannakunin markedly prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) in human plasma. Further investigation revealed that Bannakunin could inhibit the activity of the coagulation factors FXa and FXIIa, as well as the activities of elastase, trypsin, and plasma kallikrein, but it did not inhibit thrombin and FXIa. Surface plasmon resonance studies have shown that Bannakunin binds to the active sites of human elastase (KD: 1.95 nM) and human FXa (KD: 42.9 nM) with the highest affinity. Intriguingly, we observed that Bannakunin significantly inhibited clot retraction, as well as platelet aggregation and spreading. Mechanistically, Bannakunin inhibited collagen-induced platelet activation by downregulating the integrin α2β1-mediated Src/Syk/PLCγ2 signalling pathway and the release of Ca2+, TXB2 and ATP. Furthermore, Bannakunin could effectively inhibit ADP-induced platelet activation through blocking P2Y12 receptor, decreasing the activation of PI3K/Akt signalling pathways and upregulating the level of cAMP. CONCLUSIONS: These findings enrich our understanding of the anti-platelet functions of Kunitz-type inhibitors and position Bannakunin as a promising molecular template for the development of novel anti-thrombotic drugs.
Correction: The direct binding of bioactive peptide Andersonin‑W1 to TLR4 expedites the healing of diabetic skin wounds.
Li C, Xiong Y, Fu Z … +12 more , Ji Y, Yan J, Kong Y, Peng Y, Ru Z, Huang Y, Li Y, Yang Y, He L, Tang J, Wang Y, Yang X
Cell Mol Biol Lett · 2026 Feb · PMID 41709126 · Full text
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Spatiotemporal dynamics of reactive oxygen species: implications for cellular homeostasis and redox therapies.
Li Y, Zhao Q, Hu H … +1 more , Pei JF
Cell Mol Biol Lett · 2026 Feb · PMID 41703444 · Full text
Reactive oxygen species (ROS) are endogenously generated during cellular metabolism but can also be induced by environmental stressors, such as radiation, pollutants, and inflammation. While ROS are essential for cellula...
Reactive oxygen species (ROS) are endogenously generated during cellular metabolism but can also be induced by environmental stressors, such as radiation, pollutants, and inflammation. While ROS are essential for cellular function, excessive levels of ROS can inflict damage on DNA, proteins, and lipids, resulting in cellular impairment and, in severe cases, cell death. Notably, both basal ROS levels and homeostatic set point of ROS vary markedly among various subcellular compartments, with each organelle exhibiting distinct pathological consequences when its oxidative homeostasis is disrupted. Furthermore, ROS levels exhibit significant diurnal oscillations in many species, resulting in dynamic changes in cellular redox homeostasis over the 24-h cycle. Regrettably, these spatiotemporal dimensions of ROS regulation have often been overlooked in previous studies and are rarely considered in current antioxidant therapeutic strategies. This review provides a comprehensive overview of the major sites of ROS and the enzymes responsible for ROS generation and scavenging in different subcellular locations, along with their temporal variations. Additionally, the driving forces and biological functions of redox rhythms are also discussed. By integrating these insights, we aim to advance the understanding of spatiotemporal ROS regulation and provide a foundation for developing precision redox-based therapies with enhanced clinical translation.
Extrachromosomal circular DNA: a potential clinical therapeutic target in malignant tumors.
Zhang H, Zhuo E, Li M … +3 more , Feng J, Shi X, Sun X
Cell Mol Biol Lett · 2026 Feb · PMID 41691146 · Full text
Malignant tumors, commonly referred to as cancer, are pathological conditions distinguished by the unregulated growth and infiltration of malignant cells into adjacent tissues or remote organs. This uncontrolled cell pro...
Malignant tumors, commonly referred to as cancer, are pathological conditions distinguished by the unregulated growth and infiltration of malignant cells into adjacent tissues or remote organs. This uncontrolled cell proliferation results in continuous tumor cell division and proliferation in the body. The tumor invades surrounding tissues and spreads to other body parts through the bloodstream or lymphatic system. This forms distant metastases that can influence several systems and organs, seriously affecting the health and life of patients. Effective treatment methods are still lacking owing to their complex mechanism of action. With the continuous development of precision medicine, research on the correlation between extrachromosomal circular DNA (eccDNA) and malignant tumors has become a hot topic. The eccDNA is a circular DNA molecule independent of chromosomes, more stable, and less susceptible to nuclease degradation. Increasing evidence has shown that eccDNA has a function in malignant tumor heterogeneity, invasiveness, evolution, and chemical resistance. It drives tumor heterogeneity so that cancer cells can quickly adapt to treatment plans and environmental changes. Compared with linear chromosomal DNA, eccDNA has an open structure, carries active histone modifications, and can facilitate long-range gene interactions, significantly improving the transcriptional activity of genes and playing an essential regulatory role in disease progression. It also serves as a biological marker for diagnosing and predicting malignant tumors, thus attracting increasing attention. This article reviews its role, mechanism, and value in malignant tumors, providing a new perspective for diagnosing and treating this disease.
BIP orchestrates bidirectional ER protein trafficking via co-chaperone complexes.
Biadsy S, Gilad A, Madegam LA … +1 more , Igbaria A
Cell Mol Biol Lett · 2026 Feb · PMID 41691145 · Full text
BACKGROUND: Interorganellar protein redistribution is an emerging but underexplored aspect of proteostasis and cellular adaptation. Beyond canonical transcriptional and translational regulation, cells dynamically reprogr...
BACKGROUND: Interorganellar protein redistribution is an emerging but underexplored aspect of proteostasis and cellular adaptation. Beyond canonical transcriptional and translational regulation, cells dynamically reprogram the spatial distribution of proteins to rapidly respond to environmental stress. This spatial plasticity enables single gene products to acquire novel, context-dependent functions on the basis of subcellular localization. Such relocalization is particularly pronounced in pathological conditions, such as cancer and viral infections, where proteome remodeling enhances cellular survival and adaptability. We previously defined endoplasmic reticulum (ER)-to-cytosol signaling (ERCYS) as a stress-responsive mechanism that alleviates ER burden by redistributing proteins into the cytosol. Despite growing interest, the molecular mechanisms driving ERCYS and related forms of spatial proteome remodeling remain poorly defined. METHODS: To investigate these mechanisms, we employed siRNA- and CRISPR-based depletion of BIP, SGTA, and DNAJB12/14, coupled with subcellular fractionation and immunoblotting to assess protein localization under stress. Co-immunoprecipitation was used to examine protein–protein interactions, and unfolded protein response (UPR) activation was quantified via quantitative reverse transcription polymerase chain reaction (RT-qPCR). RESULTS: Our results reveal a previously unrecognized role for the UPR in mediating ER protein reflux. Specifically, we show that ATF6 and IRE1, but not PERK, are essential for initiating ERCYS. Notably, IRE1 simultaneously promotes ERCYS while suppressing BAX/BAK-mediated ER membrane permeabilization. Furthermore, we uncover a noncanonical, signaling-independent function of the ER-resident chaperone BIP in protein reflux. BIP forms a complex with membrane-bound DNAJB12/14 and cytosolic SGTA, facilitating chaperone-guided export of proteins from the ER lumen. This process depends on an intact DNAJB12 J-domain and requires BIP to originate within the ER, supporting a directional, regulated export mechanism. These findings challenge the classical view of BIP as solely mediating inward translocation and reveal a bidirectional role in protein trafficking. Our work uncovers a novel layer of UPR-regulated spatial proteome remodeling with potential relevance in cancer biology.
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