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The multiple roles of Ggt1-Cre in the generation of transgenic mice.
Feng ZS, Luo J, Chen XC … +10 more , Zhao PP, Qiu ST, Wu CY, Huang XR, Sun BC, Guo XJ, Ye ZN, Yang C, Liu HF, Tang JX
Cell Mol Biol Lett · 2026 Jan · PMID 41495633 · Full text
The Cre/loxP system continues to serve as a well-established and widely adopted strategy for generating conditional gene knockout or knock-in mouse models, facilitating precise genetic manipulations. The Ggt1 gene, which...
The Cre/loxP system continues to serve as a well-established and widely adopted strategy for generating conditional gene knockout or knock-in mouse models, facilitating precise genetic manipulations. The Ggt1 gene, which exhibits specific expression in proximal tubular epithelial cells (TECs) of the kidney, has been extensively employed as a Cre driver for tissue-specific gene targeting within these cells. In this study, to achieve conditional Fam134b knockout in proximal TECs, we generated Fam134b floxed mice and crossed them with Ggt1-Cre transgenic mice. After several generations of selective breeding, we successfully obtained conditional Fam134b knockout mice, which displayed specific deletion of the target gene in proximal TECs. This was confirmed by western blot analysis, which demonstrated a marked deficiency of the FAM134B protein in the renal cortex of these mice. During the mating experiments, we unexpectedly found that we could obtain systematic Fam134b knockout mice, suggesting that Ggt1-Cre might be expressed and functional in germ cells. Genomic and transcriptomic sequencing analysis unequivocally confirmed the deletion of exon 4, while western blot analysis revealed complete absence of FAM134B protein in both heart and kidney tissues of these knockout mice. Through the implementation of different mating strategies, we determined that Ggt1-Cre mediated gene knockout occurs in germ cells that have completed the first meiotic division, rather than in germ cells prior to this developmental stage. Furthermore, qPCR and western blot analyses demonstrated the expression of Cre driven by the Ggt1 promoter in both testes and ovaries, providing additional evidence for its germline activity. Lineage tracing experiments revealed that Ggt1-Cre is expressed in both the kidneys and testes of B6-G/R f/+; Ggt1-Cre transgenic mice, where it effectively catalyzes Cre recombinase activity, leading to the conversion of green fluorescent protein-expressing cells to red fluorescent protein-expressing cells. These findings collectively highlight that Ggt1-Cre is not only a reliable proximal TEC-specific Cre driver but also an effective germline-specific Cre driver. Consequently, it can be utilized to achieve gene knockout or overexpression in both proximal TECs and post-first meiotic division germ cells, thereby enabling in-depth in vivo functional studies of genes in these distinct cell types.
G-quadruplex structures are key regulators of mammalian spermatogenesis.
Li S, Ma Y, Shi H … +14 more , Wang R, Li C, Zhang T, Zhu C, Gu Y, Song Z, Guo H, Dong M, Li Y, Li Z, Wang MQ, Wen W, Yang F, Qin W
Cell Mol Biol Lett · 2026 Jan · PMID 41484991 · Full text
BACKGROUND: Male infertility, impacting 8–12% of couples globally, often lacks clear etiology. G-quadruplexes (G4s), noncanonical DNA structures, are implicated in genomic regulation but remain underexplored in spermatog...
BACKGROUND: Male infertility, impacting 8–12% of couples globally, often lacks clear etiology. G-quadruplexes (G4s), noncanonical DNA structures, are implicated in genomic regulation but remain underexplored in spermatogenesis. This study investigates G4 dynamics and their roles in male fertility. METHODS: We employed antibody-based staining, cleavage under targets and tagmentation (CUT&Tag) sequencing, and a novel nanobody-based proximity labeling system (nanoG4BPL) to map G4 distribution and interacting proteins in mouse testicular cells. In vivo G4 stabilization with pyridostatin and clinical analysis of testicular tissues from patients with nonobstructive azoospermia (NOA) were conducted. RESULTS: G4 structures are enriched in testicular tissues, displaying stage-specific dynamics during spermatogonial differentiation, meiosis, and spermiogenesis. Genome-wide profiling revealed the dual roles of G4s in coordinating gene expression with active epigenetic marks and facilitating genome architecture via CTCF interactions. G4 stabilization disrupted double-strand break repair during meiosis, with nanoG4BPL identifying Nijmegen breakage syndrome 1 (NBS1) as a G4-interacting protein promoting phase separation for homologous recombination. Clinically, patients with NOA exhibited significantly elevated G4 levels in spermatocytes. CONCLUSION: G4 structures are critical regulators of spermatogenesis, orchestrating gene expression, chromatin remodeling, and meiotic fidelity. Their dysregulation, particularly in patients with NOA, suggests a mechanistic link to male infertility, providing novel insights into its pathogenesis and highlighting potential avenues for future diagnostic or therapeutic exploration.
MPP7 inhibits tumor metastasis through promoting snail degradation in clear cell renal cell carcinoma.
Zhang M, Zhang J, Zhou Y … +6 more , Zhao A, Wang H, Wang B, Li J, Liu P, Yang J
Cell Mol Biol Lett · 2026 Jan · PMID 41484943 · Full text
BACKGROUND: Tumor metastasis is a major factor of high recurrence and mortality in clear cell renal cell carcinoma (ccRCC), but its underlying mechanism remains elusive. This study focuses on investigating the impact and...
BACKGROUND: Tumor metastasis is a major factor of high recurrence and mortality in clear cell renal cell carcinoma (ccRCC), but its underlying mechanism remains elusive. This study focuses on investigating the impact and underlying molecular mechanisms of MAGUK p55 subfamily member 7 (MPP7) on the metastasis of ccRCC. METHODS: The clinical significance of MPP7 in patients with ccRCC was investigated based on The Cancer Genome Atlas (TCGA), Genotype Tissue Expression Project (GTEx) databases and clinical tissue samples. Slow aggregation, microscopic photography and immunofluorescence (IF) assay were applied to assess the effect of MPP7 on intercellular adhesion, cell morphology, and cytoskeletal F-actin, respectively. Transwell and wound-healing assays were used to detect cell migration and invasion. The quantitative real-time polymerase chain reaction (qRT-PCR), western blot, IF, co-immunoprecipitation (Co-IP), and immunoprecipitation-mass spectrometry (IP-MS) were applied to elucidate the underlying molecular mechanism. RESULTS: High expression of MPP7 in ccRCC was associated with a better prognosis. Biologically, MPP7 increased intercellular adhesion, affected cell morphology, prevented the overgrowth of F-actin, and significantly inhibited the metastasis of ccRCC cells both in vitro and in vivo. Mechanistically, MPP7 competed with F-actin to bind to α-actinin-4 (ACTN4) through its GuK domain, thereby inhibiting F-actin polymerization. The reduced F-actin aggregation decreased the spatial sequestration of the E3 ligase tripartite motif-containing protein 21 (TRIM21), thus strengthening its access to Snail. The enhanced interaction between TRIM21 and Snail promoted the ubiquitin-proteasome-mediated degradation of Snail, ultimately leading to decreased migration and invasion abilities. CONCLUSIONS: Our work elucidated the role and molecular mechanism of MPP7 in migration and invasion regulation of ccRCC.
MFSD2A: a molecular nexus linking blood-brain barrier, lipid metabolism, and ischemia-reperfusion injury.
Li C, Ibrahim MM, Fang C
Cell Mol Biol Lett · 2025 Dec · PMID 41469845 · Full text
Major facilitator superfamily domain-containing protein 2A (MFSD2A) is a central molecular player in maintaining the blood-brain barrier (BBB). It exerts dual protective effects in ischemia-reperfusion injury (IRI): MFSD...
Major facilitator superfamily domain-containing protein 2A (MFSD2A) is a central molecular player in maintaining the blood-brain barrier (BBB). It exerts dual protective effects in ischemia-reperfusion injury (IRI): MFSD2A regulates the lipid composition of brain endothelial cell membranes through its sodium-dependent transport of docosahexaenoic acid-conjugated lysophosphatidylcholine (LPC-DHA); this lipid remodeling thereby maintains the characteristic low permeability of the BBB by suppressing caveolae-mediated transcytosis. This review systematically analyzes the tissue distribution patterns of MFSD2A, the protein structural features, and its biological functions both in physiological and pathological conditions. We further reveal its cell type-specific regulatory networks. Notably, acute-phase of IRI induces downregulation of MFSD2A and subsequent BBB leakage. MFSD2A not only serves as a molecular switch to enhance brain-targeted drug delivery (e.g., temporarily inhibiting its activity to improve nanoparticle transport across the BBB) but may also become a therapeutic target for maintaining BBB integrity (e.g., agonist development). This review provides a novel framework for understanding MFSD2A's multidimensional mechanisms in neurological diseases and its potential for clinical translation.
GPR43 deficiency aggravates sepsis by promoting gut microbiota-dependent barrier disruption and HIF-1α-ENO1 axis-mediated M1 polarization of macrophages.
Tang M, Li H, Tang F … +12 more , Shu Y, Meng B, Zhang Q, Li C, Xu Y, Xu Y, Pan J, Liu Y, Hu L, Wang C, Wu T, Li J
Cell Mol Biol Lett · 2025 Dec · PMID 41444511 · Full text
BACKGROUND: GPR43, a receptor for short-chain fatty acids (SCFAs), is broadly expressed in intestinal epithelial and immune cells and is essential for preserving barrier integrity and immune homeostasis. Nevertheless, ho...
BACKGROUND: GPR43, a receptor for short-chain fatty acids (SCFAs), is broadly expressed in intestinal epithelial and immune cells and is essential for preserving barrier integrity and immune homeostasis. Nevertheless, how GPR43 influences gut microbiota composition and intestinal barrier integrity while also regulating macrophage immunometabolism in the context of sepsis remains poorly understood. METHODS: A cecal ligation and puncture model was used to induce sepsis in mice. Survival, histopathology, and immune responses were compared between Gpr43−/− and wild-type mice; 16S ribosomal RNA (rRNA) sequencing and untargeted metabolomics were performed to evaluate gut microbiota composition and metabolic profiles. Antibiotic-mediated microbiota depletion and fecal microbiota transplantation were used to assess functional impacts. Bone marrow-derived macrophages were employed to investigate the effects of GPR43 deficiency on macrophage polarization. RNA sequencing, metabolic flux analysis, and Western blotting were conducted to explore the molecular mechanisms involved. Peripheral blood mononuclear cell samples from patients with sepsis were analyzed for clinical correlation. RESULTS: Gpr43−/− mice exhibited significantly reduced survival following CLP, along with impaired intestinal barrier function and elevated proinflammatory cytokine levels. Microbiota diversity and SCFA-producing bacteria were markedly decreased, accompanied by reduced SCFA levels in fecal metabolites. Fecal microbiota transplantation (FMT) partially restored gut function and survival in Gpr43−/− mice. GPR43-deficient macrophages displayed a strong M1-polarized phenotype with the upregulation of the glycolytic enzyme ENO1 and its upstream regulator HIF-1α. The inhibition of either ENO1 or HIF-1α reversed the proinflammatory phenotype. A clinical data analysis revealed that GPR43 expression was negatively correlated with IL-6, ENO1, and lactate levels. CONCLUSIONS: GPR43 exerts a dual protective role in sepsis by maintaining gut microbiota homeostasis and barrier integrity and by modulating macrophage metabolism and polarization via the HIF-1α–ENO1 axis. This study provides novel insights into the GPR43 in pathogenesis of sepsis and suggests potential therapeutic targets for intervention.
Impact of sperm fractionation on chromosome positioning, chromatin integrity, DNA methylation, and hydroxymethylation level.
Graczyk Z, Kostyk J, Pospieszna J … +5 more , Myslicka Z, Kamieniczna M, Fraczek M, Olszewska M, Kurpisz M
Cell Mol Biol Lett · 2025 Dec · PMID 41437218 · Full text
BACKGROUND: Sperm chromosomes are nonrandomly organized in the cell nucleus, which plays an important role in the regulation of early embryo development, which is determined by the specific localization of sperm chromoso...
BACKGROUND: Sperm chromosomes are nonrandomly organized in the cell nucleus, which plays an important role in the regulation of early embryo development, which is determined by the specific localization of sperm chromosomal regions carrying genes with expression crucial at the first contact with ooplasm during fertilization. Thus, the aim of this study is to determine whether the application of selective methods providing high-quality spermatozoa with good motility and/or morphology can increase the frequency of gametes with a specific positioning of chromosomes. For the first time, we used a sequential staining algorithm for consecutive analyses of the same individual spermatozoon with a fixed position, what enables one to achieve full and detailed documentation at the single cell level. METHODS: Semen samples from five normozoospermic males were collected and processed for fractionation via swim up (to select viable and motile spermatozoa) or Percoll density gradient (90%/47%; to select viable sperm with normal motility and morphology). Sperm chromatin protamination was assessed by Aniline Blue (AB) staining, and DNA fragmentation by Acridine Orange (AO) (ssDNA fragmentation) or terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay (ssDNA and dsDNA fragmentation). Then, sequential staining and analyses of the same individual spermatozoon with a fixed position on a slide were performed, in the following order: (i) fluorescence in situ hybridization (FISH) for determination of positioning of chromosomal centromeres: 4, 7, 8, 9, 18, X, and Y, with so-called linear and radial estimations applied, followed by distance measurements between selected pairs of chromosomes; and (ii) immunofluorescent (IF) measurement of global sperm DNA methylation (5mC) and hydroxymethylation (5hmC) levels, which added additional data about the epigenetic layer of the sperm chromosomes' positioning. RESULTS: Our study demonstrated that high-quality sperm selection methods significantly: (i) increased the frequency of spermatozoa with good chromatin protamination (+ ~25%) and 5mC and 5hmC DNA levels (+ ~9.5%) and (ii) reduced the rate of spermatozoa with ssDNA fragmentation (- ~65%). Motile and morphologically normal spermatozoa showed distinct chromosome repositioning with sex chromosomes shifted to the nuclear periphery, a key chromosomal region of the initial interaction with the ooplasm during fertilization process. Evaluated autosomes revealed various patterns of repositioning. CONCLUSIONS: Our findings underline the validity of methods used for selection of high-quality spermatozoa in assisted reproductive technologies (ART), also in the context of the sperm chromosomal topology and chromatin integrity, crucial at the first steps during fertilization.
Beyond the mutations: spatiotemporal regulation of CFTR by cAMP and calcium signaling in epithelial physiology and cystic fibrosis.
Varga A, Kiss A, Crul T … +3 more , Madácsy T, Pallagi P, Maléth J
Cell Mol Biol Lett · 2025 Dec · PMID 41430567 · Full text
Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the CFTR gene, but the functional expression of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl/HCO channel is determin...
Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the CFTR gene, but the functional expression of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl/HCO channel is determined by more than its genetic sequence. Beyond the well-known folding defect of the common F508del mutation, CFTR activity is dynamically modulated by a network of intracellular signaling pathways that control the channel's gating, trafficking to, and retention at the apical membrane. Foremost is the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, which drives CFTR opening via phosphorylation of its regulatory (R) domain and coordination by scaffolding proteins (e.g., A-kinase anchoring proteins (AKAPs) and Na/H exchanger regulatory factor 1 (NHERF1)). Equally important, Ca-dependent signaling cascades provide complementary fine-tuning: Ca-bound calmodulin can directly bind and increase the CFTR open probability, Ca-activated kinases such as Ca/calmodulin-dependent protein kinase II (CaMKII) and the tyrosine kinase Pyk2 (with Src) can phosphorylate CFTR through noncanonical routes, and signaling intermediates such as IP receptor binding protein released with IP(IRBIT) connect Ca release to CFTR activation. These cAMP- and Ca-driven pathways intersect in specialized subcellular nanodomains, enabling precise spatiotemporal regulation of CFTR function. Clinically, although new CFTR modulator drugs have greatly improved outcomes, their effectiveness is limited by mutation-specific responses and incomplete restoration of channel activity. Understanding how cAMP-Ca crosstalk governs CFTR in context can reveal novel therapeutic strategies targeting the channel's regulatory microenvironment. This review highlights how compartmentalized cAMP and Ca signals orchestrate CFTR function and discusses emerging approaches to harness this insight for better therapies across CF-affected organs.
SLC25A39 identified as a key regulator of hepatocellular carcinoma progression through the mitochondrial ROS-cytochrome c-caspase signaling axis.
Yuan M, Du M, Yu J … +5 more , Wang J, Xia T, Shen Q, Wang C, Li R
Cell Mol Biol Lett · 2025 Dec · PMID 41430562 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent demand for novel diagnostic and therapeutic targets. While mitochondrial carriers (MCs) pl...
BACKGROUND: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent demand for novel diagnostic and therapeutic targets. While mitochondrial carriers (MCs) play crucial roles in tumor metabolism, their specific contributions to HCC pathogenesis are poorly understood. METHODS: By leveraging multi-omics analyses, including single-cell sequencing and spatial transcriptomics, SLC25A39 was identified as a key mitochondrial carrier in HCC. To assess its diagnostic potential, receiver operating characteristic (ROC) curves were constructed across multiple retrospective independent cohorts. Functional experiments of HCC cell lines with SLC25A39 knockdown were conducted in vitro (cell proliferation, Transwell migration and invasion, and apoptosis assays) and in vivo (xenograft experiments). For deeper mechanistic insights, we employed proteomic profiling and mitochondrial functional assays. Additionally, the mitochondrial-targeted antioxidant (2-oxo-2-((2,2,6,6-tetramethyl-1-oxyl-piperidin-4-yl)amino)ethyl)triphenylphosphonium chloride (mitoTEMPO) was employed to reverse the observed phenotypes. RESULTS: SLC25A39 exhibited significant overexpression in HCC tissues, particularly in advanced-stage tumors, and demonstrated robust diagnostic accuracy (area under the curve (AUC) > 0.900 across cohorts). Deficiency of SLC25A39 markedly reduced HCC cell proliferation, migration, and invasion capabilities, triggering caspase-9/3-dependent apoptosis. Consistent with in vitro findings, xenograft models revealed impaired tumor growth upon SLC25A39 suppression. Mechanistically, SLC25A39 deficiency induced mitochondrial dysfunction, characterized by excessive mitochondrial reactive oxygen species (ROS), reduced membrane potential, diminished adenosine triphosphate (ATP) synthesis, aberrant mitochondrial permeability transition pore (mPTP) opening, and cytochrome c release. Notably, mitoTEMPO treatment reversed these effects, restoring mitochondrial redox homeostasis and rescuing malignant phenotypes. CONCLUSIONS: Our study reveals SLC25A39 as a critical regulator of HCC progression via the mitochondrial ROS-cytochrome c-caspase signaling axis, highlighting its potential as a diagnostic biomarker and therapeutic target in HCC.
PCSK9 inhibition ameliorates microplastic-induced endothelial redox imbalance via SIRT6 modulation.
D'Onofrio N, Donisi I, Del Vecchio V … +7 more , Prattichizzo F, Pellegrini V, Barbieri M, Ceriello A, Marfella R, Paolisso G, Balestrieri ML
Cell Mol Biol Lett · 2025 Dec · PMID 41430105 · Full text
BACKGROUND: Microplastics (MPs) have emerged as significant environmental pollutants, posing a threat to ecosystems and humans. The presence of MPs in atherosclerotic plaques, exacerbating cardiovascular risk, has been r...
BACKGROUND: Microplastics (MPs) have emerged as significant environmental pollutants, posing a threat to ecosystems and humans. The presence of MPs in atherosclerotic plaques, exacerbating cardiovascular risk, has been recently reported. However, the molecular mechanism underlying the effects of MPs on the vascular endothelium are still undefined. In this regard, this study aims to investigate the effects of MPs on endothelial cell function and redox state and the underlying mechanisms. METHODS: Immortalized human aortic endothelial cells (teloHAEC), human umbilical vein endothelial cells (HUVEC), and human coronary artery endothelial cells (HCAEC) were treated with MPs in the form of polyethylene (PE) and polyvinyl chloride (PVC) alone (70 µg/mL) or combined PE (30 µg/mL) + PVC (30 µg/mL) (PE + PVC) for up to 48 h. The effects of MPs on cell viability were evaluated using CCK-8, and its role in endothelial function was evaluated by flow cytometric analyses, enzyme-linked immunosorbent assays (ELISA), and XF HS Seahorse bioanalyzer. Proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were detected by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. Molecular involvement of sirtuin 6 (SIRT6) was investigated through gene silencing. RESULTS: Our study demonstrated that PE and PVC, alone or in combination, upregulated inflammatory mediators monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM1), and intercellular adhesion molecule-1 (ICAM1) (p < 0.001), modulated the expression of autophagy markers anti-autophagy related 5 (ATG5) and p62, impaired mitochondrial metabolism by reducing maximal and basal respiration and adenosine triphosphate (ATP) production (p < 0.001), promoted reactive oxygen species (ROS) accumulation (p < 0.001) and cell cycle perturbations (p < 0.01), and increased apoptosis cell death (p < 0.001). These events were accompanied by a downregulation of sirtuin 6 (SIRT6) expression (p < 0.01) and an upregulation of PCSK9, at protein and messenger RNA (mRNA) levels (p < 0.01). Treatment with the PCSK9 inhibitor (iPCSK9) evolocumab ameliorated MP-induced cellular redox state imbalance, mitochondrial metabolism alteration, and SIRT6 downregulated levels (p < 0.01). SIRT6 transient silencing experiments denied the beneficial effects of iPCSK9 treatment, indicating that the pleiotropic functions of iPCSK9 may occur, at least in part, via modulation of SIRT6 and Forkhead box O3 (FOXO3A) expression levels. CONCLUSIONS: Overall, the results indicate that PCSK9 inhibition via evolocumab exhibits substantial promise in the prevention of MP-induced endothelial dysfunction, suggesting the PCSK9-SIRT6 axis as a new promising pathway to target in preventive strategies for cardiovascular risk caused by plastic pollution.
The cancer-testis lncRNA LINC01940 promotes gastric cancer malignant progression and chemoresistance by enhancing ribosome biogenesis via TAF15-mediated NOL11 SUMOylation.
Zang W, Fan D, Lu Z … +8 more , Gao X, Xing D, Zhang G, Liu L, Yi J, Chen J, Hu Y, Xue W
Cell Mol Biol Lett · 2025 Dec · PMID 41402710 · Full text
BACKGROUND: Aberrant ribosome biogenesis promotes gastric cancer (GC) progression and contributes to chemoresistance by sustaining protein synthesis, upon which GC cell survival depends. However, the regulatory role of c...
BACKGROUND: Aberrant ribosome biogenesis promotes gastric cancer (GC) progression and contributes to chemoresistance by sustaining protein synthesis, upon which GC cell survival depends. However, the regulatory role of cancer-testis-associated long noncoding RNAs (CT-lncRNAs) in modulating ribosome biogenesis in GC remains largely unexplored. METHODS: First, we performed a screening of lncRNAs and identified CT-lncRNA LINC01940 on the basis of integrated expression and survival analyses using The Cancer Genome Atlas (TCGA) data. Subsequently, the impact of LINC01940 on GC progression and chemosensitivity was evaluated using in vitro cell functional assays, patient-derived organoid models, and in vivo subcutaneous tumor xenograft experiments. To further elucidate the underlying mechanisms, we employed a comprehensive approach combining bioinformatics analyses, RNA sequencing, fluorescence in situ hybridization, translation assays, ribosomal DNA (rDNA) transcription assays, methylated RNA immunoprecipitation, co-immunoprecipitation mass spectrometry, fluorescence multiplex immunohistochemistry, and RNA pull-down mass spectrometry. RESULTS: Normally, testis-specific LINC01940 is aberrantly upregulated in GC and associated with poor prognosis. Functional assays demonstrated that LINC01940 promotes GC cell proliferation and invasion and confers resistance to cisplatin. Mechanistically, LINC01940 is stabilized by methyltransferase 16 (METTL16)/ insulin-like growth factor 2 messenger RNA binding protein 3 (IGF2BP3)-mediated N-methyladenosine (mA) modification, which enhances its ability to act as a scaffold promoting the interaction between the small ubiquitin-like modifier 2 (SUMO2) E3 ligase TATA-box binding protein associated factor 15 (TAF15) and Nucleolar protein 11 (NOL11), promoting the SUMOylation of NOL11 and enhancing its protein stability. This, in turn, increases ribosomal DNA transcription and ribosome biogenesis, thereby promoting GC progression and chemoresistance. CONCLUSIONS: LINC01940 is a cancer-testis lncRNA that promotes GC progression and cisplatin resistance by enhancing ribosome biogenesis via the METTL16/IGF2BP3-TAF15-NOL11 axis. These findings suggest its potential as a prognostic biomarker and therapeutic target in GC.
CDCP1 allosterically regulates the AMPK α1 subunit to enhance fatty acid oxidation in osteoblasts.
Li X, Zhu W, Ma J … +4 more , Sun Z, Wang L, Jiao G, Chen Y
Cell Mol Biol Lett · 2025 Dec · PMID 41390359 · Full text
BACKGROUND: Lipid metabolism disorders in osteoblasts may lead to osteoporosis. CUB domain-containing protein 1 (CDCP1) is associated with various intracellular signaling pathways. We investigated how CDCP1 regulates lip...
BACKGROUND: Lipid metabolism disorders in osteoblasts may lead to osteoporosis. CUB domain-containing protein 1 (CDCP1) is associated with various intracellular signaling pathways. We investigated how CDCP1 regulates lipid metabolism and osteoblast function. METHODS: This study utilized gene overexpression (via lentivirus) and loss-of-function (CRISPR/Cas9-mediated knockout) techniques to investigate the involvement of CDCP1 in lipid metabolism and osteogenesis. Transcriptomic and metabolomic analyses were performed to examine the mechanism of action of CDCP1. Furthermore, proximity ligation assays, GST pull-down, and molecular docking were employed to identify the interaction between CDCP1 and AMP-activated protein kinase (AMPK). RESULTS: CDCP1 alleviated bone loss in mice. In vitro, CDCP1 promoted the phosphorylation of AMPK. Phosphorylated AMPK can enhance the activity of carnitine palmitoyltransferase, leading to increased fatty acid oxidation and promoting osteogenesis. Mechanistically, CDCP1 prevents the formation of the autoinhibitory conformation of the autoinhibitory domain by binding to the α3 helix, thereby protecting AMPK phosphorylation from self-inhibition. CONCLUSIONS: Our research revealed a new molecular mechanism linking CDCP1 and allosteric control of AMPK. These findings reveal for the first time the mechanism by which CDCP1 affects osteogenesis through lipid metabolism regulation, suggesting its potential as a therapeutic target for osteoporosis.
A novel tRF-Gly is associated with obesity development through post-transcriptional regulation of lipid metabolism.
Lei Y, Gan M, Wang K … +15 more , Liao T, Yang Y, Zhao X, Zhang X, Chen D, Wang X, Ma J, Niu L, Zhao Y, Chen L, Zhou X, Wang Y, Li M, Zhu L, Shen L
Cell Mol Biol Lett · 2025 Dec · PMID 41388249 · Full text
BACKGROUND: Obesity, characterized by excessive fat accumulation, represents a global health crisis closely linked to metabolic disorders such as type 2 diabetes, hypertension, and atherosclerosis. tRNA-derived small RNA...
BACKGROUND: Obesity, characterized by excessive fat accumulation, represents a global health crisis closely linked to metabolic disorders such as type 2 diabetes, hypertension, and atherosclerosis. tRNA-derived small RNAs (tsRNAs) have recently emerged as important epigenetic regulators, yet their roles in fat deposition remain poorly characterized. This study aims to identify tsRNAs that influence fat accumulation and to elucidate their molecular mechanisms, with a focus on tRF‑Gly‑GCC‑037 (tRF‑Gly) as a candidate regulator of adipocyte differentiation. METHODS: Visceral adipose tissue was collected from obese and lean pigs for comprehensive tRF and tiRNA sequencing. Differential expression analysis identified tRF‑Gly as a highly abundant candidate in obese samples. Functional assays in 3T3‑L1 preadipocytes included both overexpression and knockdown of tRF‑Gly, followed by lipid accumulation measurements and assessment of key adipogenic markers (CEBPα and PPARγ) by quantitative real-time PCR (qRT‑PCR) and western blot. Mechanistically, dual‑luciferase reporter assays, RNA immunoprecipitation (RIP), and nuclear-cytoplasmic protein fractionation were performed to examine how tRF‑Gly modulates the RAC1/JNK2/β‑catenin signaling axis. RESULTS: tRF‑Gly was significantly upregulated in visceral adipose tissue from obese pigs and ranked among the most abundant tsRNAs. Overexpression of tRF‑Gly in 3T3‑L1 cells and in C57BL/6 mice promoted lipid accumulation and increased CEBPα and PPARγ expression, whereas tRF‑Gly knockdown reduced lipid deposition. Mechanistically, tRF-Gly was suggested to bind RAC1 mRNA with AGO3 involvement, leading to RAC1 silencing. Consistently, RAC1 knockdown phenocopied the adipogenic effects of tRF-Gly, whereas RAC1 overexpression reversed these effects. Furthermore, RAC1 deficiency disrupted the RAC1/JNK2/β‑catenin complex, impaired β‑catenin nuclear translocation, and suppressed Wnt/β‑catenin signaling. CONCLUSIONS: Our findings demonstrate that tRF‑Gly functions as a key regulator of fat accumulation. By silencing RAC1 via AGO3, tRF‑Gly disrupts RAC1/JNK2/β‑catenin complex assembly, prevents β‑catenin nuclear translocation, and downregulates Wnt/β‑catenin signaling, thereby promoting lipid deposition. This study uncovers a novel epigenetic mechanism by which tRF‑Gly controls fat accumulation and suggests that targeting tRF‑Gly may represent a therapeutic strategy for obesity and related metabolic disorders.
Ribosomal protein RPL7A modulates lung adenocarcinoma progression via circRANBP17-UPF1-mediated SIRT6 degradation.
Zhu Y, Han J, Pan Y … +7 more , Liu Y, Zhang Z, Chen H, Zhou S, Sun Z, Liu Y, Wang Q
Cell Mol Biol Lett · 2025 Dec · PMID 41372808 · Full text
BACKGROUND: Lung cancer, primarily lung adenocarcinoma (LUAD), is the leading cause of cancer-related deaths worldwide. Despite extensive research, the mechanisms behind LUAD progression remain inadequately understood, u...
BACKGROUND: Lung cancer, primarily lung adenocarcinoma (LUAD), is the leading cause of cancer-related deaths worldwide. Despite extensive research, the mechanisms behind LUAD progression remain inadequately understood, underscoring the need for new biomarkers and therapeutic targets. Ribosomal proteins, traditionally associated with protein synthesis, are gaining recognition for their roles in tumorigenesis, though many functions remain unexplored. METHODS: This study utilized single-cell transcriptomic data and bioinformatics analyses to identify potential LUAD biomarkers. Selected biomarkers were validated using quantitative PCR (qPCR) and immunofluorescence on clinical samples. Functional roles were assessed through in vivo and in vitro assays, including migration, invasion, and proliferation studies. Mechanistic insights were gained via mRNA stability assays, RNA immunoprecipitation, fluorescence in situ hybridization, and dual luciferase reporter assays. RESULTS: RPL7A is a significant prognostic marker with elevated expression in metastatic LUAD tissues. Clinical validation shows that high RPL7A expression correlates with LUAD occurrence and poor overall survival (OS) (hazard ratio > 1). RPL7A knockdown inhibits LUAD cell migration, invasion, and proliferation, underscoring its key role in tumor progression. Mechanistically, RPL7A impacts lipid metabolism and the AKT pathway. Crucially, RPL7A regulates circRANBP17, a circRNA linked to LUAD metastasis and lipid metabolism. This interaction forms a complex with UPF1 to destabilize SIRT6 mRNA, a critical factor in lipogenesis. The resulting downregulation of SIRT6 highlights how RPL7A and circRANBP17 contribute to altered lipid metabolism and tumor progression in LUAD. CONCLUSIONS: Our findings demonstrate that RPL7A promotes LUAD progression through circRANBP17-UPF1-mediated SIRT6 degradation, positioning RPL7A as a potential therapeutic target in LUAD.
The novel circular RNA circG6pc attenuates oxidative stress and mitochondrial damage through miR-7018-5p/Aldh6a1 axis in kidney fibrosis.
Zhao X, Xiong Y, Qin X … +10 more , Hu J, Huang S, Ni X, Jian J, Yang S, Weng X, Chen H, Chen Z, Liu X, Wang L
Cell Mol Biol Lett · 2025 Dec · PMID 41351065 · Full text
BACKGROUND: Chronic kidney disease (CKD) is characterized by progressive renal fibrosis, which contributes to disease progression and ultimately leads to kidney failure. Circular RNAs (circRNAs) are key regulators in var...
BACKGROUND: Chronic kidney disease (CKD) is characterized by progressive renal fibrosis, which contributes to disease progression and ultimately leads to kidney failure. Circular RNAs (circRNAs) are key regulators in various fibrotic diseases, showing different expression patterns in different organs. However, the exact role and mechanisms of circRNAs in renal fibrosis are still not fully understood. METHODS: We analyzed circRNA expression in kidney tissues from unilateral ureteral obstruction (UUO) mice using RNA sequencing (RNA-seq). Bioinformatics analysis identified a significant downregulation of circG6pc in fibrotic kidneys. The role and mechanisms by which circG6pc inhibits renal fibrosis were explored both in vivo and in vitro. To further validate our findings, we employed gene overexpression and knockdown, along with immunohistochemistry, dual-luciferase reporter assays, RNA antisense purification (RAP) assays, RNA immunoprecipitation (RIP) assays, western blotting, and RT-qPCR. RESULTS: CircG6pc is significantly downregulated in fibrotic kidneys, and overexpression of circG6pc can notably improve renal fibrosis, mitochondrial dysfunction, and oxidative stress damage. Mechanistically, circG6pc acts as a sponge, directly binding to miR-7018-5p, thereby relieving its inhibitory effect on Aldh6a1 expression. The upregulation of Aldh6a1 promotes mitochondrial biogenesis, corrects mitochondrial dynamics imbalance, alleviates oxidative stress induced by mitochondrial dysfunction, and ultimately suppresses the progression of renal fibrosis. CONCLUSIONS: These findings reveal the molecular mechanism by which circG6pc alleviates mitochondrial dysfunction and oxidative stress through the miR-7018-5p/Aldh6a1 axis, thereby inhibiting renal fibrosis. This provides a potential new strategy for the treatment of progressive CKD.
tsRNA-3040b accumulates R-loop to regulate Trim35 transcription, which leads to disordered glycolysis and promotes PAECs proliferation.
Wang X, Li S, Hou J … +9 more , Cao S, Zhang Y, Zhang J, Wang X, Song X, Xu Y, Qi J, Xing Y, Zheng X
Cell Mol Biol Lett · 2025 Dec · PMID 41351040 · Full text
BACKGROUND: Hypoxia significantly influences the development of pulmonary hypertension (PH). However, the role of transfer RNA-derived small RNAs (tsRNAs) produced by nuclease cleavage on PH, particularly their impact on...
BACKGROUND: Hypoxia significantly influences the development of pulmonary hypertension (PH). However, the role of transfer RNA-derived small RNAs (tsRNAs) produced by nuclease cleavage on PH, particularly their impact on the proliferation of pulmonary artery endothelial cells (PAECs), remains unclear. METHODS: To detect tsRNA expression, panoramic RNA display by overcoming RNA modification aborted sequencing (PANDORA-seq) sequencing analysis and quantitative polymerase chain reaction (qPCR) were employed. The formation of R-loops between tsRNA and genomic DNA was confirmed through chromatin immunoprecipitation followed by polymerase chain reaction (ChIP-PCR) and Dot-blot analyses. Mouse PAECs and lung tissue were manipulated to either overexpress or inhibit tsRNA-3040b, followed by assessments of cell proliferation, RT-qPCR, and enzyme activity assays on three key glycolytic rate-limiting enzymes. Molecular docking, immunofluorescence and endogenous coprecipitation were used to demonstrate the colocalization of Trim35 and Wnt3a. RESULTS: The expression of tsRNA-Asp-GTC-3040b (termed tsRNA-3040b) was significantly increased in the lung tissue of a hypoxia-induced PH mouse model. By integrating database prediction with RNA sequencing, Trim35 was identified as a downstream target of tsRNA-3040b. ChIP-PCR and Dot-blot analyses using S9.6 indicated that tsRNA-3040b promoted R-loops in the genomic DNA of Trim35, thus inhibiting its transcription. Further investigation revealed that the Trim35 affected glucose metabolism levels through ubiquitinated substrate Wnt3a. Ultimately, it was elucidated that the tsRNA-3040b-Trim35-Wnt3a-glucose metabolism signaling pathway exacerbated the progression of PH. CONCLUSIONS: This study highlights the role of tsRNA-3040b in promoting PH by influencing glucose metabolism processes. These results offer a new approach to treating PH and suggest that tsRNA-3040b could serve as a potential target for diagnosing PH and related conditions.
Trigeminal nerve root compression induced neuroinflammatory response promotes mechanical allodynia through the CGRP/SP-Piezo2 axis via Ca signaling.
Liao X, Luo Z, Huang F … +7 more , Wang Y, Zeng Z, Liao W, Ou Y, Wu X, Wang F, Luo D
Cell Mol Biol Lett · 2025 Dec · PMID 41340091 · Full text
Trigeminal neuralgia (TN) is one of the most severe types of neuropathic pain, but its pathological mechanisms remain unknown. In this study, we identified a unique neuroinflammatory response induced by chronic compressi...
Trigeminal neuralgia (TN) is one of the most severe types of neuropathic pain, but its pathological mechanisms remain unknown. In this study, we identified a unique neuroinflammatory response induced by chronic compression of trigeminal root entry zone (TREZ) in a TN rat model, establishing a connection between ATP-driven intracellular pathways and Piezo2-mediated mechanotransduction. Piezo2, the pain-related neuropeptide calcitonin gene-related peptide (CGRP) receptor complex CRLR-RAMP1 and the neuropeptide substance-P (SP) receptor NK1R are co-expressed on rat Merkel cells. Protein kinase C (PKC) plays a crucial role in upregulating Piezo2 and CGRP/SP expression in both the trigeminal ganglion (TG) and whisker pad, thereby facilitating orofacial mechanical allodynia in TN rats. Furthermore, the inhibition of cAMP signaling in the whisker pads effectively alleviated mechanical allodynia, while Piezo2 knockdown in both the TG and whisker pads significantly reversed db cAMP-induced allodynia. In vitro studies demonstrated that extracellular ATP not only enhances CGRP and SP expression but also induces Piezo2 expression through Ca2+-dependent activation of ERK1/2 and p38 MAPK cascades, mediated by specific transcription factors. These findings reveal that peripheral sensitization in TN is mediated through a Ca2+-CGRP/SP-Piezo2 positive feedback loop, dependent on the neuroinflammatory response along the TG neuron–Merkel cell axis as a prerequisite condition. This discovery provides a novel insight into the pathogenesis of TN.
DNA, RNA, and histone methylation regulation enzymes and their crosstalk in colorectal carcinogenesis and progression: a review of molecular mechanisms, clinical implications, and future perspectives.
Qian S, Song H, Huang L … +6 more , Hua H, Zhang X, Li Z, Pu M, Huang H, Zhang J
Cell Mol Biol Lett · 2025 Nov · PMID 41315942 · Full text
Colorectal cancer (CRC) ranks among the most common malignant cancers of the digestive system, and its initiation and progression are closely related to both genetic and epigenetic mechanisms. Three major forms of modifi...
Colorectal cancer (CRC) ranks among the most common malignant cancers of the digestive system, and its initiation and progression are closely related to both genetic and epigenetic mechanisms. Three major forms of modifications, viz. DNA methylation, RNA m6A methylation, and histone methylation, play important roles in regulating gene expression at various stages of transcription and translation. These methylation processes are dynamic and reversible, relying on the functions of methyltransferases, demethylases, and methylation-binding proteins. Extensive studies have shown that DNA, RNA m6A, and histone methylation significantly impact multiple pathological and physiological processes in CRC, including carcinogenesis, recurrence, metastasis, resistance to both radiotherapy and chemotherapy, as well as immune regulation. Advances in high-throughput sequencing and laboratory techniques have facilitated the identification of methylation regulation enzymes with aberrant expression at the DNA, RNA, and protein levels, revealing their clinical potential for early diagnosis and treatment of CRC. The upstream regulatory mechanisms controlling these methylation regulation enzymes are crucial for understanding alterations in methylation patterns. Current evidence identifies several key mechanisms, including posttranslational modifications, epigenetic regulation, and genetic alterations, which collectively influence the expression, activity, and stability of methyltransferases, demethylases, and binding proteins. These mechanisms thereby modulate the dynamic methylation landscape across various biological contexts. Furthermore, the complex crosstalk among DNA, RNA m6A, and histone methylation is increasingly being elucidated, highlighting a need for further investigation in CRC. In this review, we systematically summarize the molecular mechanisms, clinical applications, and crosstalk involving DNA methylation, RNA m6A methylation, and histone methylation, along with their related enzymes in the development of CRC. This review aims to provide new insights and directions that underscore the significant role of epigenetic methylation modifications and their associated enzymes in CRC.
CUEDC1 promotes glycolytic metabolism reprogramming through the CUEDC1/CACNG4/PI3K axis to promote ER-positive breast cancer growth.
Lu Z, Lei M, Chen J … +9 more , Deng A, Chang C, Chen J, Meng D, Wang R, Wan X, Tu G, Liu M, Tang L
Cell Mol Biol Lett · 2025 Nov · PMID 41315933 · Full text
BACKGROUND: The reprogramming of energy metabolism, particularly glycolysis, upholds the malignancy of tumors. The relationship between CUE domain-containing protein-1 (CUEDC1) and glycolysis, along with its influence on...
BACKGROUND: The reprogramming of energy metabolism, particularly glycolysis, upholds the malignancy of tumors. The relationship between CUE domain-containing protein-1 (CUEDC1) and glycolysis, along with its influence on the development of estrogen receptor-positive breast cancer (ER+ BRCA), is not well defined. This investigation explores the functional involvement of CUEDC1 in glycolysis regulation and uncovers a previously unidentified pathway contributing to the progression of ER+ BRCA. METHODS: Immunohistochemistry, western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of CUEDC1 in ER+ BRCA tissues and cell lines. A series of molecular analyses, including dual-luciferase reporter assays, RNA-seq, and chromatin immunoprecipitation (ChIP), were performed to elucidate the potential mechanisms underlying CUEDC1’s involvement in ER+ BRCA progression. Metabolic assays focusing on glycolysis were employed to investigate the functional roles of CUEDC1 and calcium voltage-gated channel auxiliary subunit gamma 4 (CACNG4). The Connectivity Map (CMap) database was utilized to screen CUEDC1 inhibitors. RESULTS: CUEDC1 is aberrantly upregulated in ER+ BRCA tissues and cells. Increased CUEDC1 can promote enhanced tumor growth and lead to poor clinical outcomes in patients with ER+ BRCA. The MYC associated zinc finger protein (MAZ) can upregulate CUEDC1 gene transcription in ER+ BRCA cells by directly binding to its promoter. We determined that CUEDC1 directly modulated CACNG4 to enhance phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway activation, thereby facilitating tumor growth of ER+ BRCA. Clinical observations also revealed a positive correlation between CACNG4 expression and CUEDC1, with both factors being strongly associated with poor prognosis in patients with ER+ BRCA. Mechanistically, The CUEDC1/CACNG4/PI3K signal axis enhanced glycolysis through upregulating glucose transporter 1 (GLUT1), a crucial protein in glucose metabolism, thereby supporting tumor growth of ER+ BRCA. Furthermore, methotrexate was identified as a potential inhibitor of CUEDC1. Importantly, the combination of ipatasertib (a PI3K/AKT pathway inhibitor), with methotrexate effectively suppressed growth of ER+ BRCA in a mouse model. CONCLUSIONS: Our research reveals that enhanced CUEDC1 plays an essential role to ER+ BRCA cell proliferation and tumor growth via the CACNG4/PI3K axis. CUEDC1 is a promising prognostic factor of ER+ BRCA, and the CUEDC1/CACNG4/PI3K axis can serve as a potential therapeutic target for ER+ BRCA treatment.
CD209a regulates metabolic dysfunction-associated steatotic liver disease development through macrophage STAT3 signaling pathway.
Chen Y, Zhou J, Tang C … +10 more , Zhu P, Xu Z, Song X, Zhang J, Cen L, Zeng H, Ke Y, Li Y, Chen Y, Wang J
Cell Mol Biol Lett · 2025 Nov · PMID 41315908 · Full text
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern, with macrophage-driven inflammation playing a critical role in its progression. CD209a, a C-type lectin rec...
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern, with macrophage-driven inflammation playing a critical role in its progression. CD209a, a C-type lectin receptor, has been implicated in immune regulation, but its function in MASLD remains unclear. This study investigates the role of CD209a in MASLD pathogenesis, focusing on its effects on macrophage-mediated inflammation. METHODS: We analyzed CD209a expression in liver tissues from patients with MASLD and diet-induced MASLD mouse models. CD209a knockout (Cd209a−/−) mice were generated, and bone marrow transplantation was conducted to assess the impact of CD209a deficiency on hepatic steatosis, inflammation, and insulin resistance. Macrophage depletion was performed to determine whether the impact is mediated by liver macrophages. Single-cell RNA sequencing (scRNA-seq) was utilized to explore macrophage phenotypic changes and underlying signaling pathways. RESULTS: CD209a expression was significantly upregulated in livers of patients and mice with MASLD. Cd209a−/− mice exhibited aggravated hepatic steatosis, inflammation, and insulin resistance compared with wild-type controls (P < 0.05). Macrophage depletion abolished these effects, confirming a macrophage-dependent mechanism. Single-cell RNA-seq revealed that CD209a deficiency caused a shift toward a proinflammatory macrophage phenotype, with STAT3 signaling identified as a potential mediator. CONCLUSIONS: CD209a plays a protective role in MASLD. Loss of CD209a promotes macrophage-driven inflammation through STAT3 signaling and exacerbates MASLD severity. CD209a may serve as a potential therapeutic target for MASLD management, warranting further translational research.
Loss of alpha-kinase 1 contributes to the formation of congenital cataracts in mice.
Wang HS, Yang YX, Duan SS … +5 more , Long FY, Wu T, Yan NH, Li XH, Du JR
Cell Mol Biol Lett · 2025 Nov · PMID 41299222 · Full text
BACKGROUND: Alpha-kinase 1 (ALPK1), a cytosolic receptor involved in innate immune activation, promotes apical trafficking in epithelial cells. While its role in autoinflammatory disorders is known, its function in epith...
BACKGROUND: Alpha-kinase 1 (ALPK1), a cytosolic receptor involved in innate immune activation, promotes apical trafficking in epithelial cells. While its role in autoinflammatory disorders is known, its function in epithelial homeostasis remains unexplored. This study investigates ALPK1’s role in murine lens development and its pathological relevance to congenital cataracts (CCs). METHODS: We utilized ALPK1-deficient (ALPK1−/−) C57BL/6 mice and primary lens epithelial cells (LECs) with ALPK1 knockout (via lentiviral sgRNA) to analyze lens histo-morphological alterations and cellular and molecular pathologies, including apical protein transport and localization, endoplasmic reticulum (ER) stress, apoptosis, and LEC differentiation. RESULTS: We observed strong ALPK1 immunoreactivity in the LECs of C57BL/6 mice. ALPK1−/− mice developed CCs with combined Y-suture and cortical opacities, disrupted lens cell architecture, and vacuolar degeneration. Molecular dysregulation included reduced phosphorylation of myosin Ia, mislocalization of zonula occludens-1 (ZO-1) from apical tight junctions to cytoplasmic aggregates, upregulation of the endoplasmic reticulum (ER) stress marker C/EBP-homologous protein (CHOP), increased apoptosis (evidenced by TUNEL-positive cells), and disorganized interlocking patterns in lens fiber cells. Lentiviral ALPK1 re-expression in ALPK1−/− mice significantly restored lens transparency and ZO-1 apical localization, reduced CHOP expression, and suppressed apoptosis. CONCLUSIONS: This study first demonstrates that ALPK1 is critical for maintaining LEC homeostasis by regulating myosin Ia phosphorylation-dependent apical trafficking and tight junction integrity. ALPK1 deficiency disrupts these processes, leading to loss of apical polarity, ER stress-induced apoptosis, and ultimately CC formation.
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