Cell. Mol. Biol. Lett. [JOURNAL]
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200 papers
O-GlcNAc transferase governs spermatogenic mitotic-to-meiotic transition and progression by coordinating transcription and alternative splicing programs.
Ding Z, Wu C, Li M … +9 more , Hu K, Li X, Chen Z, Li K, Cheng H, Shen Q, Cao Y, Xiang H, Guo R
Cell Mol Biol Lett · 2026 Jul · PMID 42399815 · Full text
BACKGROUND: O-GlcNAcylation is a post-translational modification (PTM) uniquely catalyzed by O-GlcNAc transferase (OGT), which has been linked to tumorigenesis and neurodegeneration. However, its roles in mammalian sperm...
BACKGROUND: O-GlcNAcylation is a post-translational modification (PTM) uniquely catalyzed by O-GlcNAc transferase (OGT), which has been linked to tumorigenesis and neurodegeneration. However, its roles in mammalian spermatogenesis remain unexplored. This study aims to elucidate the functional mechanisms of OGT in spermatogenesis and male fertility. METHODS: We employed immunoprecipitation-mass spectrometry (IP-MS) to identify candidate O-GlcNAcylated substrates of OGT in juvenile mouse testes. To explore the physiological roles of OGT and O-GlcNAcylation, we constructed a mouse model with postnatal germ cell-specific deletion of Ogt via Stra8-Cre. In addition, we performed integrated bulk and single-cell RNA sequencing analyses to investigate the potential mechanisms by which OGT and O-GlcNAcylation deficiency impairs spermatogenesis. RESULTS: The results showed stage-specific OGT enrichment and O-GlcNAcylation in mouse testicular spermatogonia and early spermatocytes. Furthermore, OGT was found to interact with and O-GlcNAcylate transcription factors (e.g., HCFC1) as well as splicing regulators (e.g., SRSF1 and SF3B3) in mouse testes. Postnatal germ cell-specific Ogt deletion impaired spermatogonial differentiation, disrupted meiotic initiation and progression, and induced apoptosis, ultimately leading to male infertility. Mechanistically, Bulk RNA sequencing (RNA-seq) analysis revealed that OGT deficiency dysregulated transcriptional and alternative splicing programs, affecting genes critical for the mitotic-meiotic transition (e.g., Ythdc2 and Rbm46) and meiotic progression (e.g., Stra8, Stag3, and Syce2) in the testes. Single-cell RNA sequencing further uncovered aberrant retention of mitotic transcripts (e.g., Ccna2 and Ccnb1) in spermatocytes and impaired mRNA metabolism during spermatogonial differentiation. In addition, OGT deficiency caused cytoplasmic mislocalization and reduced expression of core transcription factors and splicing regulators in spermatocytes. CONCLUSIONS: These findings establish that OGT and its mediated O-GlcNAcylation coordinate essential gene expression and mRNA metabolism during mitotic-to-meiotic transition and meiotic progression. Moreover, our study provides mechanistic insights into the pathogenesis of male infertility associated with O-GlcNAcylation dysregulation.
Lactobacillus acidophilus abolishes oxalate-mediated renal epithelial barrier disruption and calcium oxalate monohydrate crystal adhesion to renal epithelial cells.
Putpim A, Noonin C, Chawanpaiboon P … +4 more , Pawano O, Phuangkham S, Peerapen P, Thongboonkerd V
Cell Mol Biol Lett · 2026 Jul · PMID 42399784 · Full text
BACKGROUND: It is generally known that kidney stone disease (KSD) is associated with alterations in urinary microbiome, but the roles of the urinary microbiome in KSD pathogenesis remain unclear. METHODS: This study addr...
BACKGROUND: It is generally known that kidney stone disease (KSD) is associated with alterations in urinary microbiome, but the roles of the urinary microbiome in KSD pathogenesis remain unclear. METHODS: This study addressed the impact of Lactobacillus acidophilus (a commensal bacterium found in normal urine) on renal epithelial integrity, calcium oxalate monohydrate (COM) crystal-cell adhesion, expression of membrane receptors of COM crystals, and oxalate degradation under oxalate-induced stress (a known inducer of KSD). Inner medullary collecting duct cells (mIMCD-3) were cultured for 24 h under control or oxalate-induced (by 0.6 mM sodium oxalate; NaOx) conditions without or with L. acidophilus (at 1 × 10 colony-forming unit (CFU)/ml) co-incubation. RESULTS: NaOx reduced transepithelial resistance (TER) of the mIMCD-3 monolayer and downregulated ZO-1, a tight junction (TJ) protein. Additionally, NaOx enhanced the COM crystal-binding capability of mIMCD-3 cells by upregulating a COM crystal receptor, annexin A2, on cell membranes. Such harmful effects of NaOx were abolished when mIMCD-3 cells were co-cultured with L. acidophilus. Moreover, culturing L. acidophilus in artificial urine (AU) supplemented with NaOx for 24 h revealed that the oxalate level in AU decreased, suggesting the oxalate-degrading activity of the bacterium in an AU environment. CONCLUSIONS: L. acidophilus prevented oxalate-mediated renal epithelial barrier disruption and COM crystal adhesion to renal epithelial cells by preserving ZO-1 and annexin A2 expression at their basal levels, at least in part, via its oxalate-degrading property. CLINICAL TRIAL NUMBER: Not applicable (This is not a clinical trial).
Angiogenin alleviates lipotoxicity-induced impairment of skin wound healing.
Fu M, Wang Y, Wu C … +7 more , Deng X, Zheng Z, Yu Y, Yu Y, Ma L, Feng J, Zhang C
Cell Mol Biol Lett · 2026 Jul · PMID 42399763 · Full text
Lipotoxicity-induced endothelial dysfunction impairs wound healing in obesity and type 2 diabetes, yet the underlying mechanisms remain elusive. While Angiogenin promotes endothelial function, its role under lipotoxic st...
Lipotoxicity-induced endothelial dysfunction impairs wound healing in obesity and type 2 diabetes, yet the underlying mechanisms remain elusive. While Angiogenin promotes endothelial function, its role under lipotoxic stress has been unknown. Here, we demonstrate for the first time that Angiogenin effectively protects against lipotoxicity-induced delayed skin repair. In a cellular lipotoxicity model induced by oleic and palmitic acids (OPA) using human umbilical vein endothelial cells (HUVECs), the levels of Angiogenin decreased in a time- and dose-dependent manner. Meanwhile, a similar reduction was also observed in the skin tissue of high-fat diet/streptozotocin (STZ)-induced diabetic mice and Apolipoprotein E (APOE) mice. Restoring Angiogenin levels significantly enhanced endothelial proliferation, migration, and angiogenesis, rescuing OPA-induced impairment. Through RNA-seq and subsequent validations, we provide novel mechanistic insight into Angiogenin's protective action: Angiogenin directly binds and stabilizes Caveolin-1 (Cav1) mRNA, leading to increased Cav1 expression. Critically, we show that the Angiogenin-mediated endothelial rescue is strictly dependent on this Cav1 upregulation. Furthermore, topical administration of Angiogenin peptide significantly accelerated wound closure and neovascularization in both APOE and high-fat diet/STZ-induced diabetic mice. Collectively, our study unveils a novel Angiogenin-Cav1 axis in endothelial protection, positioning Angiogenin as a promising therapeutic candidate for lipotoxicity-induced impairment of skin wound healing.
Understanding the structure of swine leukocyte antigen class I molecules.
Gao YY, Li HY, Yang SY … +6 more , Sang CJ, Cao YD, Tang Y, Li ZB, Hu GX, Gao FS
Cell Mol Biol Lett · 2026 Jul · PMID 42399753 · Full text
Swine leukocyte antigen class I (SLA-I) molecules are swine orthologs of human MHC class I molecules and are encoded by three classical loci, SLA-1, SLA-2, and SLA-3. By engaging T-cell receptors (TCRs), these cell-surfa...
Swine leukocyte antigen class I (SLA-I) molecules are swine orthologs of human MHC class I molecules and are encoded by three classical loci, SLA-1, SLA-2, and SLA-3. By engaging T-cell receptors (TCRs), these cell-surface proteins present antigenic peptides, whose binding specificity is largely dictated by the architecture of the peptide-binding groove (PBG) and its constituent pockets. Although early SLA-I research primarily emphasized molecular and functional features, recent advances in structural biology have yielded an increasing number of crystal structures of SLA-I-peptide complexes, providing critical insights into the principles of peptide presentation and T-cell recognition in pigs. In this review, we examine the structural features of SLA-I molecules, focusing on the PBG and binding pockets that accommodate peptide anchor residues. Structural studies revealed that the SLA-I PBG, while architecturally conserved, exhibits pronounced allelic polymorphism and plasticity, predominantly within its six binding pockets (A-F). A key insight is the profound functional impact of micropolymorphisms; for instance, single-residue variations in pockets such as D can dramatically alter the peptide-binding specificity and repertoire. Finally, we highlight current knowledge gaps and future research directions to facilitate the exploitation of SLA-I structural features for targeted vaccine design and immunotherapeutic development, thus addressing the challenges of porcine immune recognition.
Targeting SLK protects against cerebral ischemia-reperfusion injury by regulating USP8-mediated HIF-1α stabilization and RhoA/ROCK activation.
Wen Y, Xiong Z, Wang Z … +9 more , He Y, Wang Y, Tao Y, Huang L, Gong C, Jiang S, Du G, Chen Y, Xu T
Cell Mol Biol Lett · 2026 Jul · PMID 42387373 · Full text
INTRODUCTION: Acute ischemic stroke (AIS) represents a major global contributor to mortality and chronic disability, with few effective therapeutic targets available. Identifying druggable genes associated with AIS is th...
INTRODUCTION: Acute ischemic stroke (AIS) represents a major global contributor to mortality and chronic disability, with few effective therapeutic targets available. Identifying druggable genes associated with AIS is therefore critical for developing novel interventions. METHODS: A comprehensive approach combining Mendelian randomization, multi-omics integration, and machine learning was employed to identify candidate druggable genes. Causal relationships were confirmed through genetic colocalization, and candidate genes were further validated in a retrospective clinical cohort comprising 60 patients who experienced AIS and 30 healthy controls. Functional and mechanistic investigations were performed using a male mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model, oxygen-glucose deprivation/reperfusion (OGD/R) in HT22 cells, and 293 T cells. RESULTS: SLK emerged as a genetically causal AIS gene and a central component of the optimal predictive model. Plasma SLK levels were elevated in patients who experienced AIS, demonstrating strong diagnostic and prognostic value and serving as an independent predictor of unfavorable 3-month outcomes after adjusting for age, sex, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Knockdown of SLK conferred neuroprotection both in vivo and in vitro. SLK interacted with and phosphorylated the deubiquitinase USP8, increasing its activity and suppressing K48-linked polyubiquitination and degradation of HIF-1α. HIF-1α was stabilized following activation of the RhoA/ROCK signaling pathway, aggravating ischemic injury, whereas USP8 overexpression mitigated the neuroprotective effects of SLK knockdown. CONCLUSIONS: These findings identify SLK as a neuron-specific proischemic factor and a potential therapeutic target, elucidate the SLK-USP8-HIF-1α-RhoA/ROCK pathway as a key mechanistic pathway, and highlight plasma SLK as a promising diagnostic and prognostic biomarker with translational relevance.
Correction: 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 Jun · PMID 42380797 · Full text
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Hepatocellular carcinoma metastasis-immune microenvironment crosstalk: emerging mechanisms and immunotherapy.
Zhu W, Zhang Y, Jiang R … +2 more , Wang L, Ding J
Cell Mol Biol Lett · 2026 Jun · PMID 42366363 · Full text
Hepatocellular carcinoma (HCC), the most prevalent type of liver cancer globally, imposes a heavy burden on global public health owing to its consistently high incidence and mortality rates. Owing to the characteristics...
Hepatocellular carcinoma (HCC), the most prevalent type of liver cancer globally, imposes a heavy burden on global public health owing to its consistently high incidence and mortality rates. Owing to the characteristics of its tissue structure, HCC has a high propensity for metastasis. Unfortunately, most patients are diagnosed at the middle or advanced stage and present with metastasis. The occurrence of metastasis often indicates a severe deterioration of the condition and the loss of an opportunity for radical treatment. Thus, immunotherapy represented by immune checkpoint inhibitors (ICIs) has become the first-line treatment for patients with advanced metastasis. The tumor immune microenvironment (TIME), as the core immune component within tumors, has been confirmed to be significantly associated with metastasis through the complex crosstalk with suppressive immune cells. This crosstalk dynamically participates in the metastatic cascade of HCC, assisting tumors in completing invasion and diffusion. The goal of immunotherapy is to restore the function of exhausted immune cells in the TIME. However, the complex immunosuppressive microenvironment often weakens treatment responses, posing severe challenges to the application of immunotherapies. Accordingly, there is an urgent need to deeply investigate the crosstalk among diverse cell types within the immunosuppressive microenvironment and to systematically elucidate the impact of such intercellular crosstalk on the HCC metastasis as well as the response to immunotherapy, so as to improve the clinical benefit rate of immunotherapy for patients with metastatic HCC. This review focuses on the dual role of immune cells in HCC metastasis and the novel mechanisms by which they promote the HCC metastatic cascade. It systematically summarizes current therapeutic strategies targeting the immunosuppressive microenvironment to combat HCC metastasis. On this basis, it prospectively proposes the future development direction of immunotherapy, providing more effective guidance for the clinical diagnosis and treatment of patients with metastatic HCC.
HIF-1α enhances ferroptosis resistance in anaplastic thyroid carcinoma by suppressing ACSL4-mediated lipid metabolic homeostasis.
Xie R, Geng R, Wang Y … +9 more , Zhan C, Deng X, Duan Y, Liang J, Wang J, Liang R, Ge J, Ge M, Zhu X
Cell Mol Biol Lett · 2026 Jun · PMID 42365271 · Full text
BACKGROUND: Anaplastic thyroid carcinoma (ATC) exhibits extreme malignancy with a median survival of less than 6 months. Traditional therapeutic approaches yield limited efficacy, necessitating the urgent identification...
BACKGROUND: Anaplastic thyroid carcinoma (ATC) exhibits extreme malignancy with a median survival of less than 6 months. Traditional therapeutic approaches yield limited efficacy, necessitating the urgent identification of novel treatment strategies. The tumor hypoxic microenvironment serves as a key driver of ATC progression and drug resistance, in which the transcription factor hypoxia-inducible factor 1α (HIF-1α) orchestrates key processes in regulating tumor metabolism, immune evasion, and resistance to cell death. Ferroptosis is a novel iron-dependent form of programmed death, defined by excessive peroxidation of polyunsaturated fatty acid phospholipids (PUFA-PL) within cellular membranes. METHODS: In this study, cellular and xenograft models were employed to demonstrate that hypoxia confers ferroptosis resistance to ATC cells. Lipid metabolomics analysis revealed HIF-1α regulates lipid metabolism, and acyl-CoA synthase 4 (ACSL4) was identified as key lipid metabolism-related candidate. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were used to assess the binding of HIF-1α to the hypoxia-response element (HRE) within the ACSL4 promoter region. Flow cytometric analysis was performed to investigate how HIF-1α inhibition augments the antitumor immunogenicity of PD-1 blockade, as evidenced by enhanced intratumoral CD8 T-cell infiltration and cytokine secretion. RESULTS: This study identifies a key mechanism by which HIF-1α provides ferroptosis resistance in ATC under the intrinsically hypoxic tumor microenvironment. HIF-1α directly binds the HRE within the ACSL4 promoter, transcriptionally repressing ACSL4 and consequently curtailing PUFA-PL biosynthesis, thereby conferring ferroptosis resistance on ATC cells. In addition, combined treatment with HIF-1α inhibitor and PD-1 blockade effectively suppresses tumor progression and enhances intratumoral CD8 T-cell infiltration. CONCLUSIONS: This study elucidates the molecular mechanism by which HIF-1α mediates anti-ferroptosis in ATC through regulating lipid metabolism and proposes a promising therapeutic strategy in which HIF-1α inhibition acts synergistically with PD-1 blockade for the treatment of ATC.
Sperm surface protein disulfide isomerase ERp57 is crucial for mammalian fertilization but functions independently of IZUMO1.
Forster E, Dupuis S, Ialy-Radio C … +6 more , Serrão VHB, Yip P, Foritano M, Barbaux S, Lee JE, Ziyyat A
Cell Mol Biol Lett · 2026 Jun · PMID 42365233 · Full text
BACKGROUND: Human fertilization requires fusion of spermatozoon and oocyte membranes to form a diploid zygote, beginning with adhesion mediated by spermatozoon IZUMO1 and oocyte JUNO. Current models propose that IZUMO1 d...
BACKGROUND: Human fertilization requires fusion of spermatozoon and oocyte membranes to form a diploid zygote, beginning with adhesion mediated by spermatozoon IZUMO1 and oocyte JUNO. Current models propose that IZUMO1 dimerizes after interacting with JUNO, possibly triggered by a protein disulfide isomerase. It has been proposed that protein disulfide isomerase ERp57 is the trigger for IZUMO1 dimerization, a mechanism supported by parallels in viral entry, but direct evidence is lacking. METHODS: In vitro fertilization studies were performed for both mice and humans using ERp57 inhibitors to confirm the importance of ERp57 in mammalian fertilization. Additionally, for this study, we generated a sperm-specific ERp57 conditional knockout mouse model and performed in vivo and in vitro fertilization experiments. Biophysical assays, including dynamic light scattering and a fluorescence-based dissociation assay, were developed and utilized to investigate interactions between ERp57 and IZUMO1. Structural modeling was used to supplement the ERp57 and IZUMO1 interaction findings. RESULTS: Here, we reveal that ERp57 is crucial for mammalian fertilization but does not show evidence of any direct interaction with IZUMO1. ERp57 inhibition significantly reduces fertilization in human and mouse in vitro assays, and ERp57 spermatozoa conditional knockout (scKO) males exhibit severe hypofertility in vivo and in vitro. ERp57 localizes to the equatorial segment of human spermatozoa following the acrosome reaction, consistent with a role in gamete interaction. However, ERp57-deficient spermatozoa fail to accumulate in the perivitelline space, pointing to a role upstream of membrane fusion. Additionally, ERp57 neither promotes IZUMO1 dimerization nor facilitates dissociation of the IZUMO1-JUNO complex. Structural modeling predicted no significant interaction between ERp57 and IZUMO1, supporting experimental findings. CONCLUSIONS: These findings establish ERp57 as critical for mammalian fertilization but challenge existing assumptions about its mechanistic involvement in gamete membrane fusion. Our research contributions provide key new mechanistic insights that reexamine and reshape the current paradigms surrounding the fundamental process of sperm-egg fusion. By addressing a long-standing bottleneck in the field, our work opens new avenues of investigation that could finally lead to the identification of the elusive human sperm-egg fusogen.
Cannabidiol alleviates traumatic brain injury-induced neuronal damage and cognitive deficits by inhibiting ferroptosis via the TRPV1/MCU/PI3K/Akt pathway.
Xu Y, Li X, Gu Z … +8 more , Chen X, Zhao Y, Jia B, Wu Y, Wan R, Li Q, Wang T, Luo C
Cell Mol Biol Lett · 2026 Jun · PMID 42365227 · Full text
BACKGROUND: Traumatic brain injury (TBI) is a common surgical traumatic condition that poses a significant threat to human health and working capacity. However, effective treatments to improve its prognosis remain limite...
BACKGROUND: Traumatic brain injury (TBI) is a common surgical traumatic condition that poses a significant threat to human health and working capacity. However, effective treatments to improve its prognosis remain limited. Cannabidiol (CBD), a naturally occurring compound extracted from the cannabis plant, exhibits multiple pharmacological effects through diverse molecular targets. To date, the role and underlying molecular mechanisms of CBD in the context of TBI have not been fully elucidated. In this study, we investigated the specific effects of CBD following TBI and explored its underlying mechanisms. METHODS: An in vitro ferroptosis model was established using HT-22 cells, and an in vivo TBI model was established in mice. Techniques such as Western blotting, immunofluorescence staining, and behavioral analysis were employed to evaluate the effects of CBD on ferroptosis, pathological changes, and neurological function after TBI, as well as to explore the associated molecular mechanisms. RESULTS: CBD significantly alleviated ferroptosis, neuronal injury, and cognitive dysfunction following TBI in vitro and in vivo. Further investigation revealed that CBD mitigated mitochondrial dysfunction by reducing Ca overload via the TRPV1/MCU signaling pathway. Moreover, utilizing methodologies such as recombinant adeno-associated virus (rAAV) injection and transcriptome analysis, mitochondrial calcium uniporter (MCU) was identified as a core regulator of ferroptosis in neurons following TBI. Neuronal MCU knockdown attenuated the progression of ferroptosis and improved neurological outcomes after TBI. Finally, integrated findings confirmed that CBD inhibit ferroptosis after TBI through the TRPV1/MCU/PI3K/Akt signaling pathway. CONCLUSIONS: CBD inhibits ferroptosis, at least in part, via the TRPV1/MCU/PI3K/Akt signaling pathway, thereby alleviating TBI-induced neuronal damage and cognitive deficits. In addition, these findings indicate that CBD exhibits a potent anti-ferroptotic effect and may serve as a promising therapeutic agent for TBI.
Mitigating nucleus pulposus cell senescence in intervertebral disk degeneration: the role of nodakenin in SIRT6 and PINK1/Parkin-associated mitophagy signaling.
Zhou D, Wang L, Zhou Y … +7 more , Lv J, Song C, Mei Y, Liu T, Wu T, Yu F, Liu Z
Cell Mol Biol Lett · 2026 Jun · PMID 42363074 · Full text
Intervertebral disc degeneration (IVDD) is a common and challenging chronic condition in orthopedics, primarily characterized by the aging of nucleus pulposus cells (NPC). Current treatment strategies for IVDD, particula...
Intervertebral disc degeneration (IVDD) is a common and challenging chronic condition in orthopedics, primarily characterized by the aging of nucleus pulposus cells (NPC). Current treatment strategies for IVDD, particularly those targeting NPC senescence, remain underdeveloped. Research has shown that NPC senescence is closely associated with mitochondrial damage, leading to the accumulation of cytoplasmic reactive oxygen species (ROS) and mitochondrial DNA (mtDNA). Mitochondrial autophagy, as a key mechanism of mitochondrial quality control, regulates ROS and mtDNA levels by eliminating dysfunctional and damaged mitochondria, thereby delaying cellular aging. Notably, mitophagy signaling associated with Sirtuin 6 (SIRT6) and PTEN-induced kinase 1 (PINK1)/Parkin has been implicated in this process. Traditional Chinese Medicine (TCM), with its holistic approach and unique theoretical system of syndrome differentiation and treatment, offers significant advantages in preventing and treating degenerative diseases such as IVDD. However, research into TCM formulations aimed at NPC senescence remains limited. In preliminary studies, we observed that Nodakenin, the primary active compound from the TCM formula Duhuo Jisheng decoction (DHJSD), exerts protective effects in a SIRT6-associated manner and appears to be associated with activation of PINK1/Parkin-related mitophagy signaling. In this study, we used single-cell analysis to construct human NPC senescence and rat IVDD models, assessing mitochondrial morphology, mitochondrial membrane potential, cell senescence, and autophagy-related gene expression. We further evaluated the effects of Nodakenin (Nod) on HO-induced NPC senescence and determined the optimal intervention concentration, followed by assessment of mitochondrial phenotypes and SIRT6- and PINK1/Parkin-associated markers. These findings provide new theoretical support for the clinical application of TCM in the treatment of IVDD.
piR-26681 suppresses ovarian cancer progression by enhancing METTL3/METTL14-mediated mA modification of FBXO16 and impairing DNA repair via MORF4L1 degradation.
Wang JL, Wu QH, Yuan J … +5 more , Bao HJ, Huang XC, Cheng JC, Zhao Y, Chen S
Cell Mol Biol Lett · 2026 Jun · PMID 42343215 · Full text
BACKGROUND: Survival rates for ovarian cancer drop sharply at late-stages due to late diagnosis. Although PARP inhibitors are effective in homologous recombination-deficient (HRD) tumors, their efficacy in homologous rec...
BACKGROUND: Survival rates for ovarian cancer drop sharply at late-stages due to late diagnosis. Although PARP inhibitors are effective in homologous recombination-deficient (HRD) tumors, their efficacy in homologous recombination (HR)-proficient ovarian cancer remains limited, highlighting the need for novel molecular targets to inhibit tumor progression and improve patient outcomes. METHODS: Differentially expressed piRNAs were screened using ovarian cancer tissues from early- and advanced-stage patients. Functional studies were performed in ovarian cancer cell lines, xenograft models, and patient-derived organoids. Molecular mechanisms were investigated using RNA pulldown, RNA immunoprecipitation, MeRIP-seq, ubiquitination assays, and DNA damage analyses. RESULTS: We identified piR-26681 as a piRNA significantly downregulated in advanced-stage ovarian cancer and associated with favorable prognosis. Functional assays demonstrated that piR-26681 suppressed ovarian cancer progression in cell lines, xenograft mouse models, and patient-derived organoids. Mechanistically, piR-26681 directly interacted with METTL3 and METTL14, enhancing their interaction, reducing their ubiquitination, and thereby increasing their protein stability. This stabilization promoted global mA methylation in ovarian cancer cells. Increased mA modification subsequently enhanced the stability of FBXO16 mRNA through the mA reader IGF2BP2, leading to elevated FBXO16 expression. As an E3 ubiquitin ligase, FBXO16 further mediated the ubiquitination and degradation of MORF4L1, a key regulator of homologous recombination repair. Loss of MORF4L1 impaired HR repair, increased DNA damage accumulation, and sensitized ovarian cancer cells to the PARP inhibitor niraparib. CONCLUSIONS: Our study identifies a novel piR-26681-METTL3/METTL14-FBXO16-MORF4L1 regulatory axis that impairs DNA repair and suppresses ovarian cancer progression. piR-26681 represents a promising therapeutic target for sensitizing HR-proficient ovarian cancers to DNA-damaging therapies.
Human primordial germ cell heterogeneity in vitro is associated with distinctive biological states.
Hwang YS, Wu QY, Wamaitha SE … +1 more , Clark AT
Cell Mol Biol Lett · 2026 Jun · PMID 42343208 · Full text
BACKGROUND: Primordial germ cells (PGCs) exhibit molecular heterogeneity during development, yet whether this reflects functionally distinct states remains unclear. METHODS: We investigated the functional significance of...
BACKGROUND: Primordial germ cells (PGCs) exhibit molecular heterogeneity during development, yet whether this reflects functionally distinct states remains unclear. METHODS: We investigated the functional significance of DND1 translation heterogeneity in human PGC-like cell (hPGCLC) extended culture, using dual fluorescent reporters, transcriptomic analysis and functional assays. RESULTS: Single-cell RNA-sequencing revealed that DND1 + hPGCLCs are enriched in RNA regulatory genes including those associated with P-bodies and translational control. DND1 + cells exhibit reduced proliferation, cell cycle exit, and elevated nuclear expression P27 (CDKN1B). These cells also maintained stable expression of genes essential for germ cell differentiation. Notably, BMP2 supplementation stabilized DND1 translation without altering mRNA levels or proliferation rates. CONCLUSIONS: Together, these findings demonstrate that post-transcriptional regulation by DND1 coordinates cell cycle dynamics with distinct cellular state in human germ cells, highlighting critical translational control mechanisms in germline development.
Molecular mechanisms of FSP1-regulated ferroptosis and therapeutic implications in various cancers.
Zhang C, Sun C, Nan Y
Cell Mol Biol Lett · 2026 Jun · PMID 42337422 · Full text
Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. In addition to the canonical glutathione peroxidase 4 pathway, ferroptosis suppressor protein 1 (FSP1), also known as apoptosis-...
Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. In addition to the canonical glutathione peroxidase 4 pathway, ferroptosis suppressor protein 1 (FSP1), also known as apoptosis-inducing factor mitochondria-associated 2, functions as a major glutathione-independent suppressor of ferroptosis. Current evidence indicates that FSP1 restrains lipid peroxidation mainly through the nicotinamide adenine dinucleotide (phosphate) [NAD(P)H]-dependent coenzyme Q10 axis. FSP1 has also been implicated in the noncanonical vitamin K cycle, which further expands its redox role. Emerging studies suggest that liquid-liquid phase separation and membrane repair may broaden the functional landscape of FSP1, although these mechanisms remain less fully defined. We then summarize the multilayer regulation of FSP1 and discuss how it contributes to ferroptosis resistance, tumor adaptation, and therapeutic responses in cancer. Finally, we review current preclinical efforts to target FSP1, with emphasis on small-molecule inhibitors, mechanism-based combinations, candidate biomarkers, and major translational challenges. Together, these observations position FSP1 as an important determinant of ferroptosis resistance in cancer and a promising focus for further mechanistic and translational study.
IL17 signaling promotes oocyte developmental competence acquisition during maturation.
Zhao H, He X, Shi J … +22 more , Wu X, Liang Y, Wang X, Ao Z, Zhang X, Zhang Y, Li Y, Zhang Y, Dong Y, Peng J, Hou Y, Zhou R, Zeng F, Hong L, Gu T, Yang H, Yang J, Xu Z, Huang S, Cai G, Li Z, Wu Z
Cell Mol Biol Lett · 2026 Jun · PMID 42332549 · Full text
BACKGROUND: Defects in the acquisition of oocyte developmental competence during the maturation process causes subfertility or infertility in animals and humans. Understanding the regulatory mechanisms of oocyte maturati...
BACKGROUND: Defects in the acquisition of oocyte developmental competence during the maturation process causes subfertility or infertility in animals and humans. Understanding the regulatory mechanisms of oocyte maturation is essential for reproductive biology and medicine. Follicular fluid (FF) is an important microenvironment governing oocyte maturation. METHODS: A tandem mass tags (TMT)-based comparative FF proteomic analysis was employed to identify FF proteins that are potentially crucial for oocyte maturation. A very large number of pig and mouse oocytes (approximately 20,000) and embryos (over 13,000, including somatic cell nuclear transfer, parthenogenetic activation, and in vitro fertilization embryos) were used to investigate the effects of identified FF proteins on in vitro oocyte maturation and subsequent in vitro and in vivo embryo development. RNA sequencing, quantitative PCR, enzyme-linked immunosorbent assays, and immunofluorescence were used to study the expression patterns and action mechanisms of identified FF proteins in oocytes. In addition, intra-oocyte levels of glutathione and reactive oxygen species were measured to assess redox homeostasis. RESULTS: Interleukin 17D (IL17D) was identified as an important FF protein and it is significantly upregulated in porcine FF during oocyte maturation. IL17D promotes oocyte maturation by enhancing bidirectional communication between oocytes and cumulus cells, via upregulating CX43 expression and transzonal projections, which helps to maintain oocyte redox homeostasis and nuclear-cytoplasmic synchrony. IL17D treatment of oocytes enhances subsequent in vitro and in vivo full-term embryo development by modulating lipid metabolism and histone modification reprogramming. IL17D exerts its function via activating IL17 signaling through binding to CD93. Two other IL17 family members, IL17A and IL17F, also enhance oocyte maturation quality. IL17D displays a conserved expression pattern and function in pig and mouse oocytes. CONCLUSIONS: This study reveals the critical roles of IL17D in regulating oocyte developmental competence acquisition during maturation by activating IL17 signaling. The findings provide valuable insights into the molecular mechanisms underlining oocyte developmental potential acquisition and may help to develop methods for efficient production of oocytes for assisted reproduction.
TREM-1-dependent macrophage infiltration mediates visceral hypersensitivity via vlPAG GABAergic neuron activation in a mouse model of inflammatory bowel disease.
Zhou ZM, Song W, Guo MM … +7 more , Chu YQ, Wang LB, Cheng P, Huang JW, Su T, Huang XF, Zhang YM
Cell Mol Biol Lett · 2026 Jun · PMID 42289647 · Full text
BACKGROUND: Visceral pain is a common symptom of inflammatory bowel disease (IBD). Although triggering receptor expressed on myeloid cells-1 (TREM-1) has been shown to induce infiltration of peripheral immune cells into...
BACKGROUND: Visceral pain is a common symptom of inflammatory bowel disease (IBD). Although triggering receptor expressed on myeloid cells-1 (TREM-1) has been shown to induce infiltration of peripheral immune cells into the central nervous system, the specific contribution of peripheral monocytes/macrophages (Mo/MΦ) to visceral pain in IBD remains elusive. This study aimed to investigate the effect of TREM-1-dependent macrophage infiltration in the periaqueductal gray (PAG) on visceral pain and the underlying mechanisms in IBD. METHODS: Male C57BL/6 J or Trem1 mice were fed 2% dextran sodium sulfate (DSS) for 7 days to induce colitis. Flow sorting, flow cytometry, and western blot were employed to isolate, transfer, and detect immune cells as well as TREM-1 expression. Immunofluorescence and in vitro brain slice electrophysiology were used to assess the activity of GABAergic neurons. Visceral pain was evaluated using the abdominal withdrawal reflex (AWR) score, visceral pain threshold, and electromyography (EMG). RESULTS: Peripheral Mo/MΦ infiltration into the PAG played a dominant role in enhancing ventrolateral PAG (vlPAG) GABAergic neuronal activity in mice with acute colitis, compared with the relatively minor contributions of resident microglia and peripheral neutrophils. This promoted acute visceral pain during intestinal inflammation with visceral pain persisting into the remission phase. To validate the role of peripheral TREM-1-expressing Mo/MΦ in visceral pain, microinjection of Ly6C⁺ monocytes into the vlPAG led to activation of vlPAG GABAergic neurons and an increase in visceral pain sensitivity. Pharmacological inhibition and gene knockout of TREM-1 both reduced Mo/MΦ infiltration, leading to decreased vlPAG GABAergic neuronal activity and mitigatory visceral pain. CONCLUSIONS: Our study identifies peripheral Mo/MΦ TREM-1 as a mediator promoting visceral pain via vlPAG GABAergic neuron activation. This finding presents a promising therapeutic approach for treating acute intestinal inflammation and visceral pain in colitis, while also offering a potential target for managing chronic visceral pain that persists in patients with IBD.
PRKN mediates the ubiquitination of SCAF8 to reduce the mRNA stability of KLF5 and its transcriptional activation of EFNA3 in colorectal cancer.
Song Y, Yu Y, Zhang B … +1 more , Zhang X
Cell Mol Biol Lett · 2026 Jun · PMID 42288759 · Full text
BACKGROUND: Dysregulation in glycolysis within the tumor microenvironment is a hallmark in the context of colorectal cancer (CRC). We aimed to identify critical drivers of glycolysis in CRC and decipher the underlying me...
BACKGROUND: Dysregulation in glycolysis within the tumor microenvironment is a hallmark in the context of colorectal cancer (CRC). We aimed to identify critical drivers of glycolysis in CRC and decipher the underlying mechanism. METHODS: Through combined gene interference in CRC cells using lentivirus and treatment with glycolysis activator DASA-58, we measured glycolytic flux to evaluate how molecular mechanisms influence tumor cell activity via glycolysis. CRC cells were cocultured with NK and CD8 T cells to analyze the anti-tumor immune response. A patient-derived xenograft mouse model and a CMT93 cell-derived allograft mouse model were developed for analyzing CRC growth, metastasis, and immune evasion. RESULTS: EFNA3 was elevated in CRC tissues and cell lines. The glycolytic activity, proliferative, migratory, invasive, and pro-angiogenic effects of the CRC cells were reduced, and the anti-tumor response of the CD T and NK cells was enhanced after EFNA3 knockdown in CRC cells. Tumors formed by CMT93 cells with EFNA3 knockdown exhibited reduced metastasis and an increased proportion of anti-tumor immune cells infiltrated. Overexpression of KLF5 promoted EFNA3 transcription, and SCAF8 enhanced KLF5 mRNA stability. Downregulation of PRKN in CRC enhanced the SCAF8 protein expression through ubiquitination. PRKN upregulation blocked glycolysis and suppressed the malignant behavior of CRC cells, whereas the anticancer ability of PRKN was reversed by SCAF8/KLF5/EFNA3 overexpression. CONCLUSIONS: Activating the E3 ubiquitin ligase activity of PRKN to suppress EFNA3 expression represents a promising therapeutic strategy for the clinical treatment of CRC.
Biased signaling of β2-adrenergic receptor in physiological and pathological states.
Xu Y, Kawuribi V, Adu-Amankwaah J … +10 more , Gong Z, Li X, Lei Y, Wang Z, Sakava PB, Zhao F, Pan X, Li C, Sun H, Fu L
Cell Mol Biol Lett · 2026 Jun · PMID 42286502 · Full text
The β2-adrenergic receptor (β2AR), a pivotal member of the G protein-coupled receptor (GPCR) family, plays a crucial role in cellular signaling and is extensively involved in many physiological and pathological processes...
The β2-adrenergic receptor (β2AR), a pivotal member of the G protein-coupled receptor (GPCR) family, plays a crucial role in cellular signaling and is extensively involved in many physiological and pathological processes. Unlike the classical β1AR, the β2AR exhibits unique biased signaling properties. Selective activation of specific downstream pathways, such as the β-arrestin pathway, ERK1/2, and PI3K/Akt, is mediated by ligand binding via biased signaling by a specific G protein, resulting in distinct cellular responses. This review provides an in-depth analysis of the complex mechanisms governing biased β2AR-mediated signaling, highlighting its crucial roles in cardiovascular health, respiratory pathologies, neuroregulatory mechanisms, immunological regulation, and tumor biology. Although β2AR-biased signaling is a well-established phenomenon, its underlying mechanisms and pathophysiological implications remain incompletely elucidated compared with traditional signaling modes. This paper summarizes recent studies on the specificity of β2AR signaling and examines its potential therapeutic applications. Future research should concentrate on clarifying the structural foundations of biased signaling, developing biased ligands, and using these discoveries for precision therapeutics. The therapeutic potential of β2AR-biased signaling is being fully explored, which may open new avenues for personalized treatment of various diseases and bring breakthroughs to the field of clinical medicine.
α-tubulin N-acetyltransferase 1 regulates NCOA4-mediated ferritinophagy and protects cancer cells from ferroptosis.
Pellegrini FR, Iuzzolino A, De Palma C … +10 more , Ambrosio F, Fianco G, Naso FD, Paone A, Rinaldo S, Cutruzzolà F, Degrassi F, Strappazzon F, Stagni V, Trisciuoglio D
Cell Mol Biol Lett · 2026 Jun · PMID 42286479 · Full text
BACKGROUND: Microtubules acetylation has emerged as a key regulator of cellular homeostasis, but its roles in autophagy remain understudied. Here, we identify α-tubulin acetyltransferase 1 (ATAT1), the enzyme responsible...
BACKGROUND: Microtubules acetylation has emerged as a key regulator of cellular homeostasis, but its roles in autophagy remain understudied. Here, we identify α-tubulin acetyltransferase 1 (ATAT1), the enzyme responsible for α-tubulin K40 acetylation, as a critical regulator of NCOA4-mediated ferritinophagy and iron homeostasis in cancer cells. METHODS: Human cancer cell lines were stably or transiently silenced for ATAT1 expression. Autophagy induction was evaluated by visualizing punctate structures and by analyzing changes in autophagic marker levels. Seahorse and flow cytometry experiments were conducted to study the impact of ATAT1 silencing on cell metabolism. Additionally, analysis of iron homeostasis genes, free iron pool, as well as colocalization of NCO4A and ferritin to autophagosome were analyzed to confirm activation of ferritinophagy. Finally, we treated cells with RSL3 (a ferroptosis inducer) and ferrostatin-1 or chloroquine to understand the connection between ATAT1, autophagy, and ferroptosis-induced cell death. Genetic approaches were used to study the role of NCO4A and K40 acetylation in these pathways. RESULTS: We show that ATAT1 silencing induces an oxidative stress response accompanied by a functional autophagic flux. Notably, ATAT1-silenced cells exhibited reduced ATP production and oxygen consumption rate compared with control cells, as well as altered mitochondrial dynamics under both normal and stress conditions. Importantly, ATAT1 loss leads to intracellular iron overload by inducing NCOA4-mediated ferritinophagy, which targets the degradation of the iron storage protein ferritin, thus maintaining intracellular iron homeostasis. Activation of ferritinophagy, in turn, renders ATAT1-silenced lung cancer cells more susceptible to ferroptotic cell death. Notably, the key phenotypes observed in ATAT1-silenced cells are absent in cells with non-acetylatable α-tubulin, demonstrating a direct role for the loss of ATAT1 protein on the induction of a ferroptosis vulnerability phenotype. CONCLUSIONS: These findings challenge the traditional view of ATAT1 as a simple microtubule modifier and position this acetyltransferase as a central node in redox, metabolic, and autophagic regulation.
The NAT10/c-Myc positive feedback loop orchestrates tRNA acC modification and OTUB1-mediated protein stabilization to drive anaplastic thyroid carcinoma progression.
Wei B, Zhao H, Chang S … +1 more , Wang W
Cell Mol Biol Lett · 2026 Jun · PMID 42277649 · Full text
BACKGROUND: Epitranscriptomic regulation of tRNA modifications has emerged as an important mechanism in cancer progression by influencing oncogenic translation. Anaplastic thyroid carcinoma (ATC) is a highly aggressive m...
BACKGROUND: Epitranscriptomic regulation of tRNA modifications has emerged as an important mechanism in cancer progression by influencing oncogenic translation. Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy with limited therapeutic options. Although N-acetyltransferase 10 (NAT10) is frequently overexpressed in multiple cancers, its functional role and therapeutic potential in ATC remain unclear. METHODS: We employed integrated approaches including bioinformatics analyses,in vitro and in vivo assays, multi-omics profiling (mRNA-seq, Ribo-seq, tRNA RedaC-seq), and mechanistic studies (ChIP, LC-MS and ubiquitination assays) in ATC cell lines and xenograft models. RESULTS: NAT10 is significantly upregulated in ATC and correlates with poor prognosis. Functional assay demonstrates that NAT10 enhances ATC cell proliferation and invasion in vitro and in vivo. The targeted inhibition of NAT10 using the small molecule inhibitor remodelin effectively suppresses ATC cell growth. Mechanistically, NAT10 forms a positive feedback loop with the transcription factor c-Myc: c-Myc transcriptionally activates NAT10, whereas NAT10 is associated with enhanced translation of c-Myc in conjunction with tRNA acC modification. NAT10 depletion reduces global translation efficiency, accompanied by decreased tRNA acC levels, and also affects c-Myc protein stability via the deubiquitinase OTUB1. Moreover, combined treatment with remodelin and doxorubicin exhibits synergistic antitumor effects in both in vitro and in vivo models. CONCLUSIONS: These findings identify a NAT10/c-Myc positive feedback loop associated with tRNA acC modification and protein stabilization in ATC. Targeting this regulatory axis with remodelin in combination with doxorubicin may represent a promising therapeutic strategy.
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