Frontiers in Cell and Developmental Biology最新文献

Circular RNAs (circRNAs), a class of non-coding RNAs characterized by covalently closed-loop structures, have emerged as key regulators in the tumor immune microenvironment (TIME) of lung cancer, owing to their high stability, tissue-specific expression, and multidimensional regulatory capabilities. This review systematically synthesizes the latest research progress and elucidates the processes by which circRNAs regulate the functional states of immune cells in the TIME through diverse molecular mechanisms, including acting as competing endogenous RNAs (ceRNAs) to sequester microRNAs (miRNAs), interacting with RNA-binding proteins (RBPs), and in some cases, encoding functional polypeptides. CircRNAs possess bidirectional regulatory capacities: they can promote tumor immune evasion by modulating the expression of immune checkpoint molecules, influencing the infiltration and activity of effector immune cells (e.g., CD8⁺ T cells), recruiting immunosuppressive cells (e.g., regulatory T cells and M2-type macrophages), and regulating immune signaling pathways; meanwhile, they can also activate antitumor immune responses. Furthermore, the review explores the potential of circRNAs as liquid biopsy biomarkers for lung cancer diagnosis and prognosis, as well as their translational prospects in therapeutic strategies including vaccines, circRNA-enhanced CAR-T therapy, and formulations encoding immunomodulatory factors. Despite challenges such as complex mechanisms, low delivery efficiency, and safety concerns, the development of multi-omics technologies, novel delivery systems, and gene-editing tools provides directions for the development of precision therapies targeting circRNAs, which aim to reshape the lung cancer immune microenvironment and overcome immunotherapy resistance.

Objective: The aim of this study was to conduct a systematic investigation into the effects of ocular rotation on postoperative residual astigmatism in patients undergoing small incision lenticule extraction (SMILE).

Methods: A prospective observational cohort study involved 79 patients (153 eyes) with myopia and astigmatism who underwent SMILE surgery. Ocular rotational magnitude was measured using manual corneal and scleral marking with a slit-lamp microscopy assessment. Preoperative and postoperative (1- and 3-month) assessments included uncorrected distance visual acuity (UDVA), best-corrected visual acuity (BCVA), refractive error, and other relevant ocular parameters.

Results: Residual astigmatism showed significant correlations with ocular rotation magnitude (r = 0.429, p < 0.001), preoperative intraocular pressure (r = -0.178, p = 0.032), and preoperative cylindrical lens power (r = 0.175, p = 0.035). A multiple linear regression analysis indicated that rotation magnitude significantly impacted postoperative residual astigmatism (p < 0.001). However, preoperative intraocular pressure (p = 0.349) and spherical equivalent (p = 0.105) were not significantly related to residual astigmatism. Linear regression analysis further demonstrated significant positive correlations between rotation amplitude and various astigmatism parameters at both 1- and 3-month postoperative follow-ups (all p < 0.05). In particular, the relationships were quantified as follows: cylindrical lens (CYL [D]) (1 month: y = 7.058x + 17.480, p < 0.001; 3 months: y = 7.464x + 13.610, p < 0.001), target-induced astigmatism (TIA [D]) (1 month: y = 0.112x + 1.275, p = 0.012; 3 months: y = 0.097x + 1.217, p = 0.026), surgically induced astigmatism (SIA [D]) (1 month: y = 0.094x + 0.936, p < 0.001; 3 months: y = 0.059x + 0.911, p = 0.022), and difference vector (DV [D]) (1 month: y = 0.041x + 0.289, p = 0.005; 3 months: y = 0.037x + 0.866, p = 0.011). Notably, rotation amplitude exhibited the strongest association with postoperative CYL. Receiver operating characteristic (ROC) analysis determined the optimal thresholds for rotation magnitude in predicting residual astigmatism to be 1.5° at 1 month (AUC = 0.753; sensitivity 79.7%; specificity 58.2%) and 2.5° at 3 months (AUC = 0.929; sensitivity 92.9%; specificity 83.5%).

Conclusion: The magnitude of rotation shows a notably positive correlation with residual astigmatism during both the 1- and 3-month postoperative follow-ups. Thresholds of 1.5° (1 month) or 2.5° (3 months) prove predictive of residual astigmatism, with enhanced diagnostic precision at the later follow-up.

Bladder cancer (BC) remains a prevalent malignancy with high recurrence rates despite standard therapies. Bacille Calmette-Guérin (BCG) is the cornerstone of treatment for non-muscle-invasive bladder cancer (NMIBC); however, nearly half of patients experience relapse or develop resistance, highlighting the need for alternative strategies. Recent advances in immunotherapy have reshaped the therapeutic landscape. Immune checkpoint inhibitors (ICIs) restore T-cell function and show clinical activity in BCG-unresponsive disease. Viral vector-based approaches, including nadofaragene firadenovec and CG0070, provide localized immune activation, while cellular platforms such as CAR-T and CAR-NK therapies offer precision targeting of tumor antigens. Concurrently, nanotechnology-based delivery systems and antibody-drug conjugates (ADCs) enhance efficacy and safety by improving tumor-specific cytotoxicity. Collectively, these strategies signify a paradigm shift from traditional intravesical therapy toward personalized and durable immunotherapeutic interventions. Identification of predictive biomarkers and rational combination strategies will be critical to improving outcomes and guiding the future management of BC.

Background: Proliferative vitreoretinopathy (PVR) is a major complication of rhegmatogenous retinal detachment. Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) plays a central role in PVR pathogenesis. This study aims to investigate the effect of ADP-ribosylation factor-like 13B (ARL13B) on RPE EMT in PVR.

Methods: The expression of ARL13B in PVR specimens was analyzed by immunofluorescence (IF) staining. The effect of ARL13B on RPE EMT was assessed by IF staining and Western blot. The proliferation and migration of RPE were measured with EdU and transwell and scratch assays, respectively. The EMT-related transcriptome was analyzed by bulk RNAseq. An intravitreal injection mouse model of PVR was used to investigate the role of ARL13B in PVR formation.

Results: Immunofluorescence revealed significantly reduced ARL13B levels in α-SMA-positive cells as compared with Pan-CK-positive cells in an epiretinal membrane derived from retinal tears. During EMT, TGFβ1 treatment remarkably reduced ARL13B expression and shortened the length of cilia in RPE cells. In line with this, ARL13B knockdown (KD) decreased the length of cilia and enhanced TGFβ1-induced EMT, evidenced by morphology change and a globally upregulated EMT-related gene expression in RPEs. Moreover, ARL13B KD enhanced TGFβ1-induced RPE proliferation and migration. Consistently, ARL13B KD promoted PVR formation in vivo. Mechanistically, ARL13B KD enhanced TGFβ1 signaling by increasing the phosphorylation and expression of Smad3.

Conclusion: This study demonstrated a crucial role of ARL13B on TGFβ1-induced RPE EMT, highlighting the importance of ARL13B in PVR formation.

tRNA-derived small RNAs (tsRNAs) are a class of non-coding RNAs(ncRNAs) generated from precursor or mature tRNAs under stress conditions, such as starvation, hypoxia, or oxidative stress. They are broadly classified into a growing class of small RNAs, known as tRNA-derived RNA (tDR), tRNA-derived small RNAs or tRNA-derived fragments and tRNA-derived stress-induced RNAs (tiRNAs) based on their cleavage sites. Recent advances in high-throughput sequencing have revealed their critical roles in the reproductive system, particularly in spermatogenesis, sperm maturation, and male infertility. In females, tsRNAs are implicated in oocyte development and embryo implantation. Dysregulation of tsRNAs has also been linked to reproductive diseases, including polycystic ovary syndrome (PCOS) and endometriosis in women, and oligospermia or azoospermia in men. Mechanistically, tsRNAs regulate gene expression, mRNA stability, and translation, influencing key pathways in reproductive health and disease. Their potential as biomarkers and therapeutic targets for reproductive disorders is increasingly recognized, though further research is needed to fully elucidate their roles and clinical applications.

Introduction: Tumor necrosis factor-α (TNF-α) is considered a potential therapeutic strategy for cancers, as it exacerbates calcium influx through voltage-gated calcium channels (VGCCs), thereby inducing apoptosis. However, the mechanisms underlying TNF-α's effects at the single-molecule level remain unclear.

Methods: This study employed multiple modes of Atomic Force Microscopy (AFM) to investigate the impact of TNF-α on breast cancer cells. The measurements were performed with nanometer spatial resolution, picoNewton force sensitivity, picoAmpere current precision, and 0.1 mV surface potential accuracy.

Results: The results revealed that TNF-α treatment significantly increased the density and aggregation of VGCCs on the cell membrane while enhancing their channel activity. Concurrently, the electrical conductivity and surface potential of the membrane were elevated, collectively promoting exacerbated calcium influx.

Discussion: These findings elucidate the mechanisms by which TNF-α modulates VGCC distribution and electrophysiological properties to amplify calcium signaling, ultimately triggering apoptosis. This study provides unprecedented insights into TNF-α-induced calcium dysregulation in cancer cells at the single-molecule level, offering a novel approach for investigating apoptosis and advancing targeted therapies for breast cancer and other malignancies.

Fatty acids are not only important as energy sources, but also playing crucial roles in maintaining cellular homeostasis. However, their role in preimplantation development remains unclear. Here, we find that fatty acids gradually accumulate after 4-cell stage in mouse preimplantation development. And, the expressions of fatty acid degradation-related genes are increased along the developmental process. Inhibition of long-chain fatty acid β-oxidation (LCFAO) results in preimplantation developmental arrest, downregulated expressions of S phase-related genes, and loss of H3K18ac modification. By profiling the landscape of H3K18ac, we show that H3K18ac is enriched on the promoter regions of S phase-related genes and correlates with their expression. Together, these findings suggest that LCFAO regulate mouse preimplantation development through H3K18ac, providing additional evidence for metabolic-epigenetic crosstalk in embryonic development.

R-loops consist of double-stranded DNA-RNA hybrids and a complementary DNA strand that is displaced from the duplex. R-loops play important role in numerous normal physiological processes, including DNA methylation, chromatin remodeling, RNA editing, replication, DNA repair, immunoglobulin class switching, and chromosome segregation during cell division. However, excessive or untimely formation of R-loops can lead to replicative collapse and subsequent DNA damage, resulting in genomic instability. One type of genomic rearrangements that is strongly associated with cancer malignancy is the extrachromosomal amplification of genes on circular DNA molecules (ecDNA). These molecules are relieved of hereditary constraints and conventional segregation laws and can endow cancer cells with the ability to rapidly change their genome, thereby accelerating tumor evolution and the development of therapy resistance. Multiple lines of evidence indicate that upregulated transcription of a gene can increase its susceptibility to amplification. Although the mechanisms underlying these processes are not yet fully understood, R-loops may play an important role in initiating gene amplification. In this review, we highlight the role of R-loops in replicative collapse, double-strand breaks, and DNA damage repair. We also provide examples of gene amplifications that is known to be induced by R-loops. Finally, we discuss amplification mechanisms in which involvement of R-loops has not yet been demonstrated, but appears highly likely.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex and heterogeneous metabolic disorder where subcellular organelle dysfunction and disrupted inter-organelle communication are recognized as increasingly important drivers of pathogenesis, moving beyond traditional views focused solely on macroscopic metabolic regulation. This review systematically explores the functional impairments of key organelles-including mitochondria, the endoplasmic reticulum, lipid droplets, and autophagic pathways-to delineate their collective roles in fostering lipid metabolism imbalance, oxidative stress, and inflammation. A key innovation discussed is how the pathological dysregulation of membrane contact sites (MCSs) acts as a pivotal mechanism decoupling organelle function and accelerating disease progression. We conclude that therapeutic strategies aimed at restoring cellular metabolic flexibility-by precisely modulating MCSs, activating clearance pathways, and restoring energy metabolism-represent a promising new paradigm for treating MASLD, particularly in patient populations unresponsive to current therapies.