Cell. Mol. Biol. Lett. [JOURNAL]
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200 papers
Chemokines and chemokine receptors in metabolic dysfunction-associated steatohepatitis: pathogenic mechanisms and clinical implications.
Yin M, Zhang Y, Liu S … +1 more , Li X
Cell Mol Biol Lett · 2026 Apr · PMID 42021137 · Full text
Metabolic dysfunction-associated steatohepatitis (MASH), an advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD), is characterized by persistent hepatic inflammation and fibrosis and frequen...
Metabolic dysfunction-associated steatohepatitis (MASH), an advanced stage of metabolic dysfunction-associated steatotic liver disease (MASLD), is characterized by persistent hepatic inflammation and fibrosis and frequently progresses to cirrhosis or hepatocellular carcinoma. Chemokines and their receptors, which drive disease progression and complications by orchestrating immune cell recruitment, inflammatory responses, and fibrotic processes, are central to the pathophysiology of MASH. Emerging evidence also underscores their functions as active metabolic integrators, reciprocally linking systemic insulin resistance to hepatic inflammation. This review aims to elucidate the pathogenic contributions of key chemokines such as chemokine (C–C motif) ligand (CCL)2, CCL5, CCL20, and chemokine (C–X–C motif) ligand (CXCL)10 in MASH by assessing their dual potential as therapeutic targets and non-invasive biomarkers for early detection. We also survey the current landscape of chemokine-directed therapies to critically evaluate both their efficacy and limitations. Although early clinical trials targeting chemokine pathways have yielded mixed outcomes, emerging research underscores the complexity of chemokine signaling and highlights multiple opportunities for stage-tailored and sex-specific interventions. Therefore, a deeper understanding of chemokine function in MASH holds considerable promise for facilitating the development of targeted, multidimensional treatment strategies, paving the way for personalized management of this progressive liver disorder.
LUCAT1 drives arecoline-induced head and neck cancer progression via STAT1-mediated transcriptional regulation.
Huang HH, You GR, Chang JT … +1 more , Cheng AJ
Cell Mol Biol Lett · 2026 Apr · PMID 42021133 · Full text
BACKGROUND: Areca nut chewing is a major environmental risk factor for head and neck cancer (HNC), particularly in Southeast Asia. However, the molecular mechanisms linking areca nut exposure to malignant progression rem...
BACKGROUND: Areca nut chewing is a major environmental risk factor for head and neck cancer (HNC), particularly in Southeast Asia. However, the molecular mechanisms linking areca nut exposure to malignant progression remain poorly understood. Long noncoding RNAs (lncRNAs) have emerged as critical regulators of oncogenesis, but their role in areca nut-associated HNC remains unexplored. METHODS: We performed functional assays, transcriptomic profiling, and bioinformatics analyses to investigate the role of the lncRNA LUCAT1 in arecoline-treated HNC cells. Cell motility, epithelial–mesenchymal transition (EMT), reactive oxygen species (ROS) levels, and therapeutic resistance were assessed following LUCAT1 knockdown or overexpression. We identified upstream regulators of LUCAT1 through promoter analysis, transcription factor knockdown, and pharmacological inhibition. RESULTS: LUCAT1 expression was significantly upregulated by arecoline exposure and promoted cell motility, EMT, ROS clearance, and resistance to radiotherapy and chemotherapy. Knockdown of LUCAT1 reversed these malignant phenotypes and suppressed antioxidant enzyme expression, partly through modulation of the p38 MAPK pathway. Transcriptomic and promoter analyses identified STAT1 as a key transcription factor activated by arecoline via muscarinic acetylcholine receptor (mAChR) signaling. Functional rescue experiments confirmed that LUCAT1 acts downstream of STAT1 to sustain arecoline-induced tumor aggressiveness. CONCLUSIONS: Our findings define a novel mAChR–STAT1–LUCAT1 regulatory axis that mediates areca nut-induced malignant progression in HNC. This study not only reveals a critical molecular pathway linking environmental carcinogen exposure to oncogenic transcriptional reprogramming but also highlights LUCAT1 as a promising target for therapeutic intervention in high-risk patients with HNC.
ENTPD3 as a novel regulator of endometrial receptivity: suppressing EMT via the ATP-P2Y2 axis in patients with recurrent implantation failure.
Mo D, Zeng Z, Luo Y … +10 more , Ma W, Hu KL, Qin X, Lin M, Niu H, Sui X, Yu Y, Zhou P, Yang Y, Li R
Cell Mol Biol Lett · 2026 Apr · PMID 42014997 · Full text
BACKGROUND: Recurrent implantation failure (RIF) remains a major challenge in assisted reproductive technology and is primarily attributed to impaired endometrial receptivity. Despite its clinical significance, the preci...
BACKGROUND: Recurrent implantation failure (RIF) remains a major challenge in assisted reproductive technology and is primarily attributed to impaired endometrial receptivity. Despite its clinical significance, the precise mechanisms underlying RIF remain inadequately understood. METHODS: Single-cell RNA sequencing (scRNA-seq) was performed on endometrial samples from patients with RIF and healthy controls during the secretory phase using the 10X Genomics Chromium platform. The expression and localization of ectonucleoside triphosphate diphosphohydrolase 3 (ENTPD3) in the window of implantation (WOI) in the endometrium were examined using real–time quantitative polymerase chain reaction (RT–qPCR), western blotting, and immunohistochemistry (IHC). A mouse model with ENTPD3 overexpression was utilized to assess embryo implantation in vivo, and an in vitro blastocyst adhesion assay was performed to evaluate endometrial receptivity. Additionally, Ishikawa cells were transduced with an ENTPD3 recombinant adenovirus to explore the underlying molecular mechanisms. RESULTS: ENTPD3 expression was significantly upregulated in the endometria of patients with RIF during the WOI, and its apical surface localization in endometrial epithelial cells was confirmed by single-cell data and IHC. Functional studies demonstrated that ENTPD3 overexpression impaired endometrial receptivity by suppressing epithelial–mesenchymal transition (EMT). In vivo, ENTPD3 overexpression markedly reduced endometrial receptivity and inhibited embryo implantation in mice. Consistently, in vitro assays revealed that ENTPD3 overexpression diminished blastocyst adhesion to endometrial epithelial cells. Mechanistically, ENTPD3 hydrolyzes ATP, thereby suppressing EMT via the P2Y2 signaling pathway and ultimately disrupting endometrial receptivity. CONCLUSIONS: Dysregulated ENTPD3 expression contributes to RIF pathogenesis by impairing endometrial receptivity through ATP hydrolysis-mediated suppression of EMT via P2Y2 signaling. These findings highlight ENTPD3 as a potential therapeutic target for improving implantation success in affected patients.
Endothelial JAML inhibits inflammation and atherosclerosis through TRIM25-mediated STAT1 ubiquitination.
Han Q, Xue F, Li J … +11 more , Wu Z, Guo C, Zhang Y, Wu X, Yan J, Guo D, Zou X, Zhang W, Zhang M, Zhang C, Yang J
Cell Mol Biol Lett · 2026 Apr · PMID 42001028 · Full text
BACKGROUND: Atherosclerosis is a chronic inflammatory disease initiated by endothelial dysfunction. Junctional adhesion molecule-like protein (JAML) is known to regulate inflammatory responses; however, its function in v...
BACKGROUND: Atherosclerosis is a chronic inflammatory disease initiated by endothelial dysfunction. Junctional adhesion molecule-like protein (JAML) is known to regulate inflammatory responses; however, its function in vascular endothelial cells and atherosclerosis remains unclear. This study aimed to investigate the function of endothelial JAML in atherosclerosis and to uncover the molecular mechanisms involved. METHODS: We generated mice with specific deletion of JAML in endothelial cells and fed them a high-fat diet to induce atherosclerosis, then assessed plaque formation in the aortic root and entire aorta. In parallel, endothelial cells were treated with tumor necrosis factor alpha, and the effects of increasing or silencing JAML on adhesion molecule expression were evaluated, with protein interactions analyzed by co-immunoprecipitation and immunoblotting. RESULTS: JAML exhibited downregulation in endothelial cells within both atherosclerotic lesions and cultured cells subjected to inflammatory stimuli. In mice, the loss of JAML resulted in exacerbated atherosclerotic progression, characterized by larger plaque formation, increased vascular inflammation, and increased macrophage infiltration. Conversely, overexpression of JAML attenuated the expression of adhesion molecules. Mechanistically, JAML was found to promote the degradation of signal transducer and activator of transcription 1 (STAT1) by facilitating its interaction with the E3 ubiquitin ligase tripartite motif-containing 25. This interaction led to ubiquitin-mediated proteolysis of STAT1, independent of alterations in its gene expression levels. CONCLUSIONS: These findings suggest that endothelial JAML holds significant promise as a novel therapeutic target for the prevention and intervention of atherosclerosis.
High-temperature ssBP-LAMP breaks the barrier of nonspecific amplification and unlocks the full potential of LAMP diagnostics.
Simões RS, Bule P, Fontes CMGA … +1 more , Teodoro JS
Cell Mol Biol Lett · 2026 Apr · PMID 41992105 · Full text
BACKGROUND: Loop-mediated isothermal amplification (LAMP) is a highly attractive nucleic acid detection method for decentralized molecular diagnostics, but its broader adoption has been limited by unpredictable nonspecif...
BACKGROUND: Loop-mediated isothermal amplification (LAMP) is a highly attractive nucleic acid detection method for decentralized molecular diagnostics, but its broader adoption has been limited by unpredictable nonspecific amplification (NSA). Here, we dissect the fundamental determinants of LAMP specificity and present a new high-temperature ssBP-LAMP technique to suppress NSA without compromising assay sensitivity or speed. METHODS: Ubiquitous bioinformatic tools for prediction and design of primer sets and their characteristics were employed to generate a panel of 21 primer sets targeting diverse bacterial, viral, fungal, and human targets. Fluorometric ssBP-LAMP was implemented with a series of coordinated modifications, from increased temperature (only possible owing to a novel, engineered thermostable strand displacement Bst polymerase enzyme) to fine-tuning of additives and auxiliary enzymes. Finally, proof-of-concept validation using both fluorometric and colorimetric approaches for ssBP-LAMP was performed, and their resistance to common inhibitors of molecular diagnostics was evaluated. RESULTS: We show for the first time that primer design alone is insufficient to ensure specificity, and bioinformatic predictions are insufficient predictors of efficiency and, more importantly, of specificity, even when using elevated reaction temperatures. This suggests that NSA frequently originates during the thermal ramp-up phase, before the assay reaches its operational temperature. To address this, we employed a thermolabile single-stranded DNA-binding protein (ssBP) from bacteriophage T7, which transiently sequesters primers during temperature ramp-up. When combined with conventional LAMP primers and elevated assay temperatures (≥ 68 °C), ssBP consistently suppressed NSA across all tested targets. This approach translated directly to both liquid and lyophilized master mixes, enabling highly specific ssBP-LAMP detection by real-time fluorescence and colorimetry. These formulations retained robust sensitivity (down to 10–100 copies/reaction for real-time detection), eliminated false positives, and exhibited tolerance to clinically relevant inhibitors such as plasma, hemoglobin, saliva, and urine, especially in real-time fluorescence detection. CONCLUSIONS: Together, the results establish high-temperature ssBP-LAMP as a rapid (< 15 min), specific, inhibitor-tolerant, and highly adaptable molecular diagnostic technology that overcomes key limitations of conventional LAMP while achieving analytical performance comparable to qPCR, with broad relevance for both clinical and point-of-care testing.
The role of the cGAS/STING pathway in skeletal muscle regeneration: modulation of inflammation, macrophage polarization, and oxidative stress.
Liu X, Wang H, Xu M … +8 more , Wang H, Wang H, Fang W, Li M, Huang J, Wang H, Yu Y, Zhu L
Cell Mol Biol Lett · 2026 Apr · PMID 41975278 · Full text
BACKGROUND: Skeletal muscle regeneration is essential for restoring muscle structure and function following injury. This process is influenced by various signaling pathways. Recent studies suggest that cGAS/STING signali...
BACKGROUND: Skeletal muscle regeneration is essential for restoring muscle structure and function following injury. This process is influenced by various signaling pathways. Recent studies suggest that cGAS/STING signaling, which is known for its role in innate immunity, may also play a crucial role in tissue regeneration. This study investigated the regulatory role of the cGAS/STING pathway in skeletal muscle regeneration. METHODS: Skeletal muscle injury was induced via intramuscular injection of cardiotoxin (CTX) into the tibialis anterior (TA) muscle of mice. Genetic knockout models of cGAS and STING, as well as treatment with a STING agonist (DMXAA), were used to explore the role of the pathway in muscle regeneration. Histological analysis, flow cytometry, RNA extraction, and gene expression analysis were performed to evaluate muscle tissue morphology, macrophage infiltration, and the expression of inflammatory and oxidative stress markers. RESULTS: STING expression was significantly increased following injury. Treatment with a STING agonist impaired muscle regeneration, characterized by reduced muscle fiber dimensions, elevated pro-inflammatory macrophage infiltration, and increased oxidative stress. In contrast, cGAS or STING knockout enhanced muscle regeneration and promoted the accumulation of anti-inflammatory macrophages. CONCLUSIONS: The cGAS/STING pathway plays a critical role in skeletal muscle regeneration by influencing inflammation, macrophage polarization, and oxidative stress.
NK-cell-derived exosomes exert antitumor potency via miR-140/XYLT1/HSPG2 axis.
Li D, Chen Z, Liang H … +9 more , Li Q, Mao X, Zhang B, Gu W, Xiao Y, Xiong XD, Zhou D, Deng Y, Cai M
Cell Mol Biol Lett · 2026 Apr · PMID 41965528 · Full text
Non-small cell lung cancer (NSCLC) remains a leading cause of global mortality, necessitating novel therapies. This study investigated the therapeutic role of natural killer cell-derived exosomes (NK-Exo), whose antitumo...
Non-small cell lung cancer (NSCLC) remains a leading cause of global mortality, necessitating novel therapies. This study investigated the therapeutic role of natural killer cell-derived exosomes (NK-Exo), whose antitumor mechanisms are incompletely understood. Exosomes were isolated from interleukin (IL)-2-independent NK-92MI cells via differential ultracentrifugation and characterized by nanoparticle tracking, electron microscopy, and western blotting. They exhibited cup-shaped morphology (50–150 nm), expressed CD81/TSG101, and demonstrated selective cytotoxicity against tumor cells (A549, A375) but not nontumor cells (293 T) in vitro; this effect was corroborated in patient-derived lung organoids. Small RNA sequencing revealed miR-140-3p as highly enriched in NK-Exo, and its expression correlated with improved survival in patients with NSCLC. Functional validation showed that overexpressing miR-140-3p enhanced NK-Exo cytotoxicity and directly inhibited cancer cell migration and invasion, whereas inhibiting miR-140-3p promoted tumor growth. Mechanistically, miR-140-3p directly targeted xylosyltransferase 1 (XYLT1), as confirmed by dual-luciferase assay, leading to reduced levels of heparan sulfate proteoglycan 2 (HSPG2). Knockdown of XYLT1 phenocopied the tumor-suppressive effects of miR-140-3p, while supplementation with heparan sulfate reversed them. In a Lewis lung carcinoma mouse model, intratumoral delivery of NK-Exo, miR-140-3p mimic, or XYLT1 Small interfering RNA (siRNA) significantly inhibited tumor growth and alleviated splenomegaly. In conclusion, NK-Exo deliver miR-140-3p to suppress tumors via the novel miR-140-3p/XYLT1/HSPG2 axis, presenting a promising therapeutic strategy for cancer.
Hedgehog pathway activity downstream of Smoothened is regulated specifically by basal ciliary PKA.
Zhang H, Chen S, Huang Z … +7 more , Ben J, Wei Y, Chen G, Wu C, Xie H, W Ingham P, Zhao Z
Cell Mol Biol Lett · 2026 Apr · PMID 41957701 · Full text
BACKGROUND: Effectors of the vertebrate Hedgehog (HH) signaling pathway are organized within primary cilia (PC). Protein kinase A (PKA), a ubiquitously distributed kinase in most cells, functions as a specific negative r...
BACKGROUND: Effectors of the vertebrate Hedgehog (HH) signaling pathway are organized within primary cilia (PC). Protein kinase A (PKA), a ubiquitously distributed kinase in most cells, functions as a specific negative regulator of the HH pathway. Its functional specificity in the HH pathway has been suggested to be controlled by cyclic adenosine monophosphate (cAMP) in PC. However, the regulation of PKA and its roles in PC remain unclear, partly owing to the lack of observations regarding PKA localization in PC during the resting state of HH signaling, as well as conflicting reports on the dynamic changes in ciliary cAMP levels and HH pathway activity. Here, we clarify that PKA with basal activity in PC specifically regulates the HH pathway and confirm that Smoothened (SMO)-mediated HH pathway activation may not be fully dependent on its inhibition of ciliary PKA activity. METHODS: To investigate the role of PKA during HH pathway, we have developed an improved ciliary-localized Förster resonance energy transfer (FRET)-based A-kinase activity probe (Nphp3N-AKAR2-CR) for real-time monitoring of ciliary PKA activity in both cultured cells and living embryos. Additionally, by leveraging a highly efficient ciliary targeting peptide (Nphp3N), we specifically delivered PKA variants to either PC or cytoplasm, thereby dissecting the regulatory roles of PKA in the HH pathway across different subcellular compartments. Furthermore, we performed constitutively active SMO variant (SMOA1)–forskolin (FSK) titration assays to validate the dose-dependent relationship underlying SMO-mediated inhibition of PKA. RESULTS: Basal ciliary PKA activity in cells was detected by this probe, despite the absence of observable PKA catalytic subunits in PC. Only ciliary-targeted PKA can modulate the HH pathway, even when PC integrity is disrupted. Notably, ciliary PKA activity is barely changed by either inhibition or activation of the HH pathway at the level of SMO. Furthermore, even low concentrations of FSK efficiently inhibit the HH pathway in the presence of SMOA1. CONCLUSIONS: A basal level of PKA localized in PC but not cytoplasm specifically regulates HH signal transduction, and SMO-mediated activation of the HH pathway may not be solely attributed to the direct regulation of ciliary PKA activity.
Restoration of lysosomal membrane integrity in cell models of Pompe disease depends on fatty acid synthase and its product palmitic acid.
Le Guillou E, Segaloni A, Gadault A … +10 more , Oliveira Dias C, Henneman NF, Su M, Nemazanyy I, Hifdi N, Nivet-Antoine V, Laemmerhofer M, Hnia K, Caillaud C, Panasyuk G
Cell Mol Biol Lett · 2026 Apr · PMID 41957585 · Full text
BACKGROUND: Lysosomal storage disorders (LSDs) are rare inherited diseases caused by mutations in genes encoding lysosomal proteins, leading to substrate accumulation and lysosomal dysfunction. Whether this build-up comp...
BACKGROUND: Lysosomal storage disorders (LSDs) are rare inherited diseases caused by mutations in genes encoding lysosomal proteins, leading to substrate accumulation and lysosomal dysfunction. Whether this build-up compromises lysosomal membrane integrity remains an open question. In this study, we aimed to investigate the presence of lysosomal membrane damage in LSD cells and to identify mechanisms that could reveal potential strategies for improvement of lysosomal function. METHODS: Primary skin fibroblasts from patients with LSDs were used to evaluate lysosomal integrity and function. Lysosomal immunopurification enabled lipidomic and proteomic profiling, complemented by viral transduction for targeted protein expression at lysosomal membranes. Pharmacologic and metabolite treatments were applied in loss-of-function and rescue analyses. Microscopy-based approaches were used to assess lysosomal activity, membrane damage, and integrity. As a complementary model, we employed conditional mouse embryonic fibroblasts (MEFs) lacking class 3 phosphoinositide 3-kinase (PI3K-3), which exhibit lysosomal dysfunction and autophagy defects characteristic of LSDs. RESULTS: In Pompe disease, caused by mutations in the acid alpha-glucosidase gene, glycogen accumulation aggravates persistent lysosomal membrane damage. Moreover, using loss- and gain-of-function models of PI3K-3, we showed that its product, phosphoinositide-3-phosphate (PI3P), was essential for preserving lysosomal membrane integrity. Notably, Pompe patient fibroblasts exhibited chronic lysosomal damage, marked by increased galectin-3 (GAL-3) recruitment and reduced levels of lysosome-associated PI3K-3. Targeted restoration of PI3K-3 at lysosomal membranes rescued this defect and stabilized membrane integrity. Proteomic analyses following genetic or pharmacologic inhibition of PI3K-3 revealed a striking downregulation of fatty acid metabolism, including depletion of fatty acid synthase (FASN). We further demonstrated that PI3K-3 and FASN functionally interacted to maintain lysosomal integrity in Pompe cells. Supplementation with the FASN product palmitate reproduced the protective effect of PI3K-3 targeting, enhancing lysosomal proteolysis and restoring autophagic flux. Importantly, palmitate treatment also improved lysosomal function in fibroblasts from patients with Gaucher disease and type 2 neuronal ceroid lipofuscinosis, extending the relevance of this mechanism across LSDs. CONCLUSIONS: These findings in cell models of LSDs uncover a link between PI3K-3, fatty acid metabolism, and lysosomal membrane integrity. They provide a basis for future in vivo validation of PI3K-3 activation and metabolic modulation as adjuvant treatments to improve lysosomal function in LSDs.
A tRNA-derived fragment tRF3019a promotes LUAD metastasis by stabilizing hnRNPK and enhancing MYH11 expression.
Li X, Cui W, Wang Z … +8 more , Chen D, Kuang Z, Jiang J, Lai Y, Zhang X, Duan C, Zhang C, Li X
Cell Mol Biol Lett · 2026 Apr · PMID 41937164 · Full text
BACKGROUND: tRNA-derived fragments (tRFs) have been shown to play important regulatory roles in cancer biology. However, the impact of tRFs on lung adenocarcinoma (LUAD) remains largely unexplored. METHODS: The different...
BACKGROUND: tRNA-derived fragments (tRFs) have been shown to play important regulatory roles in cancer biology. However, the impact of tRFs on lung adenocarcinoma (LUAD) remains largely unexplored. METHODS: The differential expression of tRF3019a, a tRNA fragment derived from tRNA-Ala (AGC), was identified through database mining and subsequently validated by quantitative reverse transcription PCR (qRT–PCR) in pathological tissues obtained from 100 patients with LUAD. The role of tRF3019a in LUAD metastasis was assessed through both in vitro and in vivo experiments. A comprehensive investigation of its regulatory function involved RNA pulldown assays, mass spectrometry, RNA immunoprecipitation (RIP), western blotting, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and rescue assays. RESULTS: tRF3019a expression was significantly elevated in LUAD tumor tissues and was associated with advanced disease stage and metastatic progression. Higher tRF3019a expression correlated with shorter overall survival and disease-free survival. Functionally, tRF3019a enhanced LUAD cell migration and invasion both in vitro and in vivo. Mechanistically, tRF3019a interacted with heterogeneous nuclear ribonucleoprotein K (hnRNPK) and inhibited its ubiquitin-mediated proteasomal degradation, leading to increased hnRNPK protein stability. This was accompanied by changes in epithelial–mesenchymal transition (EMT)-associated markers, including increased N-cadherin and vimentin and decreased E-cadherin. Furthermore, tRF3019a enhanced hnRNPK-associated transcriptional regulation of the myosin heavy chain 11 (MYH11) gene, contributing to the pro-metastatic phenotype of LUAD cells. CONCLUSIONS: tRF3019a promotes LUAD progression and metastasis by stabilizing hnRNPK and enhancing hnRNPK-associated transcriptional regulation of MYH11. These findings identify a previously unrecognized tRF3019a–hnRNPK–MYH11 regulatory axis involved in LUAD metastasis.
EIF4A3-induced circUBAC2 promotes lung cancer progression via regulation of the Hippo signaling pathway.
Meng F, Zhang X, Wang X … +10 more , Qiu B, Zeng D, Huang X, Liu J, Wu H, Cui K, Zhong B, Liu W, Gong X, He X
Cell Mol Biol Lett · 2026 Apr · PMID 41937152 · Full text
BACKGROUND: Circular RNAs (circRNAs) are stable noncoding RNAs involved in cancer, yet their mechanisms in lung adenocarcinoma (LUAD) remain unclear. This study explores the oncogenic role of circUBAC2 in LUAD progressio...
BACKGROUND: Circular RNAs (circRNAs) are stable noncoding RNAs involved in cancer, yet their mechanisms in lung adenocarcinoma (LUAD) remain unclear. This study explores the oncogenic role of circUBAC2 in LUAD progression. METHODS: Differentially expressed circRNAs were screened by microarray. circUBAC2 expression/location was analyzed via quantitative real-time PCR (qRT-PCR), RNA in situ hybridization (RNA-ISH), and fluorescence in situ hybridization. Functional impacts were evaluated through wound healing, Transwell, EdU, colony formation, and xenograft models. circUBAC2 targets were identified by RNA-sequencing/proteomics, with protein interactions assessed via western blotting, immunoprecipitation, and ubiquitination assays. Molecular interactions were examined using dual luciferase, chromatin Immunoprecipitation (ChIP), and RNA pull-down. RESULTS: circUBAC2 was upregulated in LUAD tissues and correlated with poor prognosis. It promoted LUAD cell proliferation, migration, and invasion in vitro, as well as tumor growth/metastasis in vivo. Mechanistically, circUBAC2 competitively bound 14-3-3 to release YAP for nuclear translocation while scaffolding OTUB1–YAP interactions to enhance YAP deubiquitination and stabilization, collectively activating TEAD-mediated oncogenic transcription. EIF4A3 facilitated circUBAC2 biogenesis by binding flanking intronic regions. CONCLUSIONS: circUBAC2 drives LUAD progression via YAP signaling, positioning it as a therapeutic target and prognostic biomarker.
Integrated analysis of single-cell RNA sequencing, transcriptomics, and thermal proteome profiling identifies PLCG1 as the therapeutic target of isopimpinellin in treating rheumatoid arthritis.
Cui H, Wang N, Min F … +14 more , Pei H, Wang Y, Li H, Wan Q, Meng Y, He M, Lv X, Xing L, Li Z, Pan T, Li R, Wen W, Kong X, Bian Y
Cell Mol Biol Lett · 2026 Apr · PMID 41935283 · Full text
BACKGROUND: Isopimpinellin (ISOP), derived from Toddalia asiatica (L.) Lam, is thought to possess anti-inflammatory potential. However, the effects of ISOP on rheumatoid arthritis (RA) and corresponding mechanisms remain...
BACKGROUND: Isopimpinellin (ISOP), derived from Toddalia asiatica (L.) Lam, is thought to possess anti-inflammatory potential. However, the effects of ISOP on rheumatoid arthritis (RA) and corresponding mechanisms remain unclear. METHODS: We evaluated the therapeutic effect of ISOP on RA using the collagen-induced arthritis (CIA) rat model. Subsequently, we determined the potential mechanisms of ISOP by combining single-cell RNA sequencing of rat synovial tissue in vivo with transcriptome analysis of macrophages in vitro. Molecular docking, thermal proteome profiling, cellular thermal shift assays, and drug affinity responsive target stability were then employed to identify the molecular targets of ISOP. Finally, we validated this target and explored the interaction between macrophages and RA-fibroblast-like synoviocytes (FLS) in vitro. RESULTS: We found that ISOP improved pathological changes in CIA rats. Mechanistically, ISOP inhibited macrophage migration and M1 macrophage polarization, and downregulated Spp1 expression. Furthermore, ISOP restrained the RAS/ERK pathway in M1 macrophages. Importantly, PLCG1 is a direct target of ISOP. Silencing PLCG1 reduced the related inhibitory effects of ISOP on M1 macrophage polarization. In addition, the supernatant of macrophages treated with ISOP reduced the proliferation and activation of RA-FLS. Silencing PLCG1 eliminated the regulatory effects of ISOP in the macrophage-RA-FLS co-culture system. CONCLUSIONS: ISOP exerts its anti-RA effects by targeting PLCG1 to inhibit the production of SPP1 in M1 macrophages.
ADAM9 in tumor biology: molecular functions, clinical implications, and therapeutic targeting.
Ho KH, Wu CJ, Yang YC … +1 more , Chien MH
Cell Mol Biol Lett · 2026 Apr · PMID 41933290 · Full text
A disintegrin and metalloproteinase 9 (ADAM9), a member of the ADAM family, is expressed across multiple organs and is crucial to multiple physiological processes. Increasing evidence implicates ADAM9 in cancer progressi...
A disintegrin and metalloproteinase 9 (ADAM9), a member of the ADAM family, is expressed across multiple organs and is crucial to multiple physiological processes. Increasing evidence implicates ADAM9 in cancer progression through extracellular matrix (ECM) remodeling, protein shedding, and tumor microenvironment modulation. This study comprehensively reviews the literature on the clinical significance of ADAM9 and the mechanistic roles of ADAM9 in cancer. The results of our pan-cancer analysis demonstrated that ADAM9 is frequently upregulated and consistently associated with poor prognosis across tumor types. The results of in silico analyses also revealed that increased ADAM9 expression is correlated with an immunosuppressive tumor microenvironment and the activation of cancer-promoting pathways, such as cell cycle progression, epithelial-mesenchymal transition (EMT), and metabolism. This study also reviewed therapeutic strategies targeting ADAM9 and evaluated their potential in cancer treatment. This review provides insights into ADAM9 as both a biomarker of malignancy and a promising therapeutic target.
DYRK2 drives renal fibrosis through CDK1-dependent G2/M phase dysregulation in tubular epithelial cells.
Bai F, Wang C, Wang S … +5 more , Zhao Y, Feng F, Yu K, Liu L, Yang X
Cell Mol Biol Lett · 2026 Apr · PMID 41933287 · Full text
BACKGROUND: Renal fibrosis is a common pathological characteristic of chronic kidney disease (CKD) and serves as the critical prognostic indicator for renal outcomes. However, current therapeutic strategies for managing...
BACKGROUND: Renal fibrosis is a common pathological characteristic of chronic kidney disease (CKD) and serves as the critical prognostic indicator for renal outcomes. However, current therapeutic strategies for managing renal fibrosis remain limited. Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2), an evolutionarily conserved kinase, is implicated in cell proliferation and apoptosis in various pathological contexts. However, its role in renal fibrosis is unclear. METHODS: The expression of DYRK2 and association with renal injury and fibrosis were assessed in pathological sections from various CKD subtypes. Two independent renal fibrosis models, namely unilateral ureteral obstruction-induced and aristolochic acid-induced mice, were used to investigate the role of DYRK2 in renal fibrosis. Integrated multi-omics approaches, including RNA sequencing (RNA-seq) and liquid chromatography-tandem mass spectrometry (LC–MS/MS) interactomics, were employed to elucidate the underlying mechanisms. RESULTS: Clinically, DYRK2 expression was elevated in patients with CKD and strongly correlated with histopathological fibrosis, glomerular filtration rate (GFR) decline, and an increased urine albumin-to-creatine ratio (UACR) in patients. In experimental fibrosis models, DYRK2 expression was markedly upregulated, which was particularly observed in proximal tubules. Silencing DYRK2 attenuated tubular injury, collagen deposition, and fibroblast activation. RNA sequencing revealed significant enrichment of oxidative stress-related pathways upon DYRK2 silencing. Functional studies demonstrated that DYRK2 ablation restored redox homeostasis in renal tubular epithelial cells (RTECs). Moreover, Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment showed that DYRK2 ablation restored the G2/M phase of the cell cycle in RTECs, reflected by a decrease in the cyclin B1/cyclin D1 ratio, as well as reduced levels of p21 and phosphorylated histone H3 (P-H3). Mechanistically, mass spectrometry screening and co-immunoprecipitation assays revealed an interaction of DYRK2 and cyclin-dependent kinase 1 (CDK1). Notably, DYRK2 promoted phosphorylation of CDK1 at the Thr14 site, thereby inhibiting its activity. The increased Thr14 phosphorylation of CDK1 almost reversed the protective effects of DYRK2 loss on transforming growth factor (TGF)-β1-induced tubular cell injury and fibrosis. CONCLUSION: These findings highlight the pivotal role of DYRK2 in driving G2/M dysregulation in RTECs under fibrotic conditions. Targeting DYRK2 may offer a promising and novel therapeutic strategy for renal fibrosis.
Ribbon constrains dendritic pruning via actin scaffolding and exocyst complex.
Wang W, Wang S, Yuan Y … +1 more , Rui M
Cell Mol Biol Lett · 2026 Apr · PMID 41928094 · Full text
BACKGROUND: During animal development, neurons selectively remove superfluous synaptic connections, strengthen key synapses, and optimize neural circuits in the brain, which is a core mechanism for fine-tuning the develo...
BACKGROUND: During animal development, neurons selectively remove superfluous synaptic connections, strengthen key synapses, and optimize neural circuits in the brain, which is a core mechanism for fine-tuning the development of the nervous system. Drosophila class IV dendritic arborization (C4da) sensory neurons undergo dendrite-specific pruning during development. Nevertheless, the cell-autonomous inhibitory mechanisms of dendritic pruning in C4da neurons are largely unknown. METHODS AND RESULTS: Here, we discovered Ribbon (Rib), a nuclear BTB-domain protein, whose malfunction in C4da neurons causes a precocious occurrence of dendritic pruning. Our study further shows that the regulation of dendritic pruning by Rib is dependent on Akt/Tor signaling. Moreover, actin polymerization factors and exocyst complex subunits are also involved in repressing dendritic pruning and function as downstream effectors of Rib and Akt/Tor signaling. CONCLUSIONS: Overall, the present study reveals a cell-autonomous inhibitory mechanism of Rib in dendritic pruning, with a perspective to provide new insights into neurodevelopment and the pathogenesis of relevant neurological disorders.
Palmitoylation-dependent regulation of innate and adaptive immunity: molecular insights and translational opportunities.
Zhou B, Zhang B, Qi Y … +10 more , Li S, Liu T, Li T, Wang Y, Wang H, Lu J, Cao F, Kang X, Kong E, Liang Y
Cell Mol Biol Lett · 2026 Apr · PMID 41928090 · Full text
Immune cells orchestrate organismal defense through pathogen surveillance, tissue homeostasis, and immune tolerance, with innate and adaptive subsets coordinating context-specific responses. The dynamic lipid modificatio...
Immune cells orchestrate organismal defense through pathogen surveillance, tissue homeostasis, and immune tolerance, with innate and adaptive subsets coordinating context-specific responses. The dynamic lipid modification, S-palmitoylation (often referred to simply as palmitoylation), regulates membrane trafficking, signal transduction, and protein–protein interactions by spatiotemporally controlling the localization, stability, and activity of immune mediators. Dysregulation of this process in immune cells contributes to pathologies including immunosuppression, chronic inflammation, and autoimmunity. This review synthesizes current knowledge on how palmitoylation governs immune cell development, subset-specific functions, and immune-mediated pathologies—encompassing metabolic disorders, infectious diseases, autoimmune disorders, and cancer. We further explore the diagnostic and therapeutic potential of targeting palmitoyltransferases, depalmitoylases, and palmitoylation-dependent immune checkpoints to restore immune equilibrium. By integrating mechanistic insights into palmitoylation-dependent immune regulation with translational applications, this work underscores the potential of palmitoylation-centric biomarkers and therapies to transform immunological diagnostics and treatment.
Targeting mutant p53 in cancer: from mechanistic insights to therapeutic strategies.
Wu HH, Leng S, Eisenstat DD … +2 more , Sergi C, Leng R
Cell Mol Biol Lett · 2026 Mar · PMID 41917811 · Full text
The tumor suppressor p53, often referred to as the “guardian of the genome,” is mutated in more than half of human cancers. These mutations have a significant impact on cancer biology and response to therapy. p53 mutatio...
The tumor suppressor p53, often referred to as the “guardian of the genome,” is mutated in more than half of human cancers. These mutations have a significant impact on cancer biology and response to therapy. p53 mutations involve a range of changes that interfere with DNA binding, eliminate tumor suppressor functions, and, in many cases, confer dominant-negative or gain-of-function characteristics that actively promote oncogenesis. These mutations are closely linked to poor clinical outcomes and resistance to standard treatments. This review examines the impact of p53 mutations on cancer therapy in various ways. In chemotherapy and radiotherapy, loss of wild-type p53 impairs DNA damage responses, whereas mutant forms often contribute to treatment resistance. Additionally, p53 status influences responses to targeted therapies and immunotherapies, thereby affecting patient outcomes and prognoses. Importantly, ongoing clinical trials are beginning to integrate p53 mutational status as a predictive biomarker for therapy selection. Strategies aimed at restoring p53 activity are gaining increasing popularity in the development of treatments. These approaches include gene therapy to reintroduce the wild-type gene, targeted degradation of mutant p53 proteins, and small molecules designed to refold or reactivate mutant p53. In addition, synthetic lethality frameworks are being utilized to exploit vulnerabilities specific to tumors with p53 mutations, as well as interventions that target downstream effectors of p53 pathway. Together, these strategies represent a significant shift in precision oncology.
Targeting fibroblast activation protein-α to treat renal fibrosis.
Gong L, Lu X, Ma N … +15 more , Lu T, Gong Y, Hao L, Xu W, Zhang Q, Chen X, Mo Q, Tan J, de Paula Lemos H, Speechley A, Tu W, Cai J, Huang L, Zhu W, Wu S
Cell Mol Biol Lett · 2026 Mar · PMID 41906119 · Full text
BACKGROUND: Renal fibrosis is the common outcome of chronic renal disease. Currently, there are no effective therapies. Fibroblast activation and extracellular matrix accumulation are key processes driving renal fibrosis...
BACKGROUND: Renal fibrosis is the common outcome of chronic renal disease. Currently, there are no effective therapies. Fibroblast activation and extracellular matrix accumulation are key processes driving renal fibrosis. METHODS AND RESULTS: Fibroblast activation protein (FAP) is highly induced in injured kidneys, and immunofluorescence staining revealed that FAP is mainly expressed in Platelet-derived growth factor receptor-beta (PDGFRβ)+ and alpha-smooth muscle actin (α-SMA)+ myofibroblasts in kidney samples from mice with renal fibrosis and patients with chronic kidney diseases or post-acute kidney injury. In this study, targeting FAP as a strategy for treating renal fibrosis is tested using two preclinical animal models: the mouse models of unilateral ureteral obstruction and unilateral renal ischemia–reperfusion. Adoptive transfer of T cells expressing chimeric antigen receptor specific to FAP or administration of an FAP inhibitor (SP-13786) significantly alleviated kidney fibrosis in both mouse models. Eliminating FAP+ fibroblasts using chimeric antigen receptor T-cell (CAR-T) therapy or inhibiting the FAP prevented fibroblast overactivation, proliferation, and migration, promoted apoptosis, and effectively suppressed other myofibroblast populations. CONCLUSIONS: Overall, we report herein that targeting FAP offers a novel promising treatment approach for renal fibrosis.
CDH4/UBA1/RBMX axis promotes polycystic ovary syndrome progression through YAP1 activation.
Xu N, Yu B, Li Y … +6 more , Yang Y, Wang Y, Fang L, Wu H, Luan Y, Yin C
Cell Mol Biol Lett · 2026 Mar · PMID 41882537 · Full text
BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of childbearing age. In addition, it is a heterogeneous disease with numerous etiologies, multiple levels, and uneven manifes...
BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of childbearing age. In addition, it is a heterogeneous disease with numerous etiologies, multiple levels, and uneven manifestation. In patients with PCOS, the number of antral follicles is abnormally increased. Several studies indicate and preliminarily support that Hippo pathway abnormalities may contribute to PCOS development by promoting excessive antral follicle proliferation. Moreover, the key Hippo pathway effector, Yes-associated protein 1 (YAP1), contributes to PCOS susceptibility. Furthermore, dysfunction of ovaries in patients with PCOS leads to irregular granulosa cell (GC) growth, which can affect ovulation and cause infertility. Nevertheless, few studies have investigated the key mechanism regulating Hippo activation in PCOS. METHODS: Hippo-associated gene sets and publicly available sequencing databases were used to screen potential PCOS-driving genes, and cadherin 4 (CDH4, R-cadherin) was found to exhibit abnormally high expression in ovarian granulosa cells. Functional studies were conducted to investigate the effects of CDH4 inhibition on PCOS-related ovarian function. RESULTS: A lower CDH4 level ameliorated ovarian function in patients with PCOS by decreasing chronic inflammation and modulating mitochondrial function and apoptosis in GCs. Mechanistically, CDH4 interacts with UBA1 and RBMX, increasing the ubiquitin-dependent degradation of RBMX and finally resulting in the transcriptional activation of YAP1. These results highlight the pivotal role of CDH4 in PCOS, which is achieved through the regulation of the Hippo–YAP1 signaling axis. CONCLUSIONS: This study demonstrates that CDH4 plays a pivotal role in PCOS pathogenesis by regulating the Hippo–YAP1 signaling axis. The finding that reduced CDH4 could enhance the prognosis of individuals with PCOS by regulating ovarian GC activity could potentially inform novel treatment strategies.
Therapeutic potential of 20-Hydroxyecdysone in pulmonary arterial hypertension: involvement of Mas receptor and PI3K-Akt pathway.
Lu T, Jia W, Wang Y … +9 more , Ma Y, Song C, Du F, Gao H, Jin X, Li H, Liu C, Jin H, Lin Y
Cell Mol Biol Lett · 2026 Mar · PMID 41876978 · Full text
BACKGROUND: 20-Hydroxyecdysone (20E), a natural polyhydroxylated steroid found in various edible plants, exhibits diverse pharmacological effects. Pulmonary arterial hypertension (PAH) remains challenging to treat owing...
BACKGROUND: 20-Hydroxyecdysone (20E), a natural polyhydroxylated steroid found in various edible plants, exhibits diverse pharmacological effects. Pulmonary arterial hypertension (PAH) remains challenging to treat owing to its multifactorial pathogenesis. Although recent advances, including US Food and Drug Administration (FDA)-approved therapies such as sotatercept, have improved outcomes, no curative treatment is currently available. This study aims to investigate the preventive and therapeutic effects of 20E on PAH and elucidate its underlying molecular mechanisms. METHODS: A monocrotaline-induced PAH rat model was utilized to evaluate the efficacy of 20E. The Mas receptor antagonist A779 and agonist AVE0991 were used to investigate the role of Mas in PAH progression and 20E-mediated prevention. Molecular docking and pull-down assays were conducted to confirm the interaction between 20E and the Mas receptor. In vitro, the effects of 20E on Ang II-induced proliferation and migration of human pulmonary arterial smooth muscle cells (HPASMCs) were assessed. The PI3K-Akt signaling pathway was analyzed by western blot. RESULTS: 20E prevented PAH at 30 mg/kg and 90 mg/kg, while 90 mg/kg rescued preexisting PAH. The protective effects of 20E were attenuated by A779. 20E upregulated Mas receptor expression and directly bound to it. In vitro, 20E inhibited Ang II-induced HPASMC proliferation and migration. It also downregulated p-PI3K, p-Akt, and p-mTOR while restoring P27 and P21 expression. Furthermore, knockdown of the Mas in HPASMCs abolished the effects of 20E on these processes. CONCLUSIONS: 20E inhibits PASMC proliferation and migration through Mas-dependent mechanisms and modulation of downstream PI3K-Akt signaling, thereby effectively preventing and rescuing PAH. It may be a promising pharmacological candidate for PAH treatment.
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