Cell and Bioscience最新文献

Primary cilia are solitary, non-motile, microtubule-based organelles that protrude from the surface of most vertebrate cells, functioning as highly specialized sensory and signaling compartments. Architecturally, they comprise the basal body, transition zone, and 9 + 0 axoneme, which together establish a biochemically distinct and selectively permeable domain, spatially segregated from the cytoplasm. This compartmentalization enables primary cilia to integrate and modulate diverse signaling cascades, including Hedgehog, Wnt, Notch, TGF-β/BMP, Hippo, cGAS-STING, calcium, GPCR, and phosphoinositide cascades, thereby coordinating developmental programs, tissue patterning, and homeostatic regulation. Ciliogenesis proceeds through basal body docking to the plasma membrane, vesicle fusion, and axoneme elongation, a sequence precisely orchestrated by bidirectional trafficking machinery of intraflagellar transport (IFT). The dynamic equilibrium between ciliary assembly and disassembly is closely coupled to cell cycle progression and signaling flux. Within the confined ciliary compartment, molecular gating at the transition zone and the polarized trafficking of receptors and effectors confer stringent control over pathway specificity and signal fidelity. Disruption of primary cilia perturbs this spatiotemporal precision, resulting in defective signal integration and a broad spectrum of disorders collectively termed ciliopathies, which range from congenital malformations to metabolic and neoplastic diseases. This review summarizes recent advances in elucidating the structural architecture, biogenesis, and signaling functions of primary cilia, highlighting their critical roles in vertebrate biology and disease.

The distribution of adipose depots in different body parts affects pig production value and human health, governed by complex epigenomic mechanisms. Limited studies on pig adipose depots have hindered the genetic improvement of fat-related economic traits and their biomedical applications. To address this issue, we generated epigenomic maps for backfat, belly fat, groin fat, and intermuscular fat (IMF) in Meishan pigs, integrating ChIP-seq, ATAC-seq, RNA-seq, Hi-C, and public whole-genome sequencing data. Our results reveal that belly/backfat share similar chromatin states, while groin fat/IMF exhibit distinct H3K27ac modification, super-enhancer (SE) dynamics, and open chromatin landscapes compared to belly/backfat. The spatially specific expressions of adipogenic transcription factors (TFs), such as lipid synthesis-related TFs PPARA and SOX6, which are highly expressed in back/belly fat, and adipocyte differentiation TF KLF4 was driven by a groin fat specific SE, underlie these chromatin state disparities. These results also suggest enhanced lipid synthesis in belly/backfat and adipocyte differentiation in groin fat. Moreover, candidate functional variants identified in IMF-gained H3K27ac peaks are primarily associated with meat quality traits. Genes linked to pig backfat thickness may also serve as candidate genes for human obesity due to the conserved cis-regulatory elements and gene expression patterns between humans and pigs. Overall, our epigenomic landscape enhances understanding of adipose depot regulation in mammals, facilitating cross-species insights and precision breeding.

Background: Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid progression and the frequent emergence of resistance to standard chemotherapeutic agents such as cisplatin (DDP) and etoposide (VP16), resulting in poor clinical outcomes.

Methods and results: To elucidate mechanisms underlying chemoresistance, we conducted a genome-wide CRISPR/Cas9 knockout screen, which identified the histone demethylase KDM6B as a critical mediator of drug resistance in SCLC. Genetic silencing of KDM6B significantly reduced IC₅₀ values of DDP and VP16, particularly in H69-AR cells, and enhanced chemotherapy-induced apoptosis. Consistently, pharmacological inhibition of KDM6B using the dual KDM6A/B inhibitor Gskj1 markedly potentiated the effects of DDP and VP16, while exhibiting minimal cytotoxicity as monotherapy. Overexpression of KDM6B rescued the chemosensitizing effect of Gskj1, thereby excluding confounding contributions from KDM6A. In vivo, the combination of Gskj1 with chemotherapy synergistically suppressed tumor growth without detectable systemic toxicity. To explore the downstream regulatory pathways, we performed transcriptome analysis via RNA-seq followed by KEGG pathway enrichment analysis, which revealed that Gskj1 treatment modulates key oncogenic signaling pathways. Integration of RNA-seq with H3K27me3 ChIP-seq data identified EGR3 as a direct epigenetic target of KDM6B inhibition. STRING analysis further suggested that EGR3 is co-expressed with c-FOS. Functional assays, including qRT-PCR, Western blotting, Co-immunoprecipitation (Co-IP), and dual-luciferase reporter assays, confirmed that EGR3 transcriptionally activates c-FOS, establishing an EGR3/c-FOS regulatory axis downstream of KDM6B. Mechanistically, inhibition of this axis enhanced chemosensitivity by promoting apoptosis, as evidenced by activation of caspase signaling, and by inducing ferroptosis through downregulation of GPX4, upregulation of ACSL4, lipid peroxidation, and modulation of HO-1. Rescue experiments with Z-VAD and ferrostatin-1 further validated that both apoptosis and ferroptosis contribute to the chemosensitizing effects of KDM6B inhibition.

Conclusion: Finally, in vivo experiments using patient-derived xenograft (PDX) models demonstrated that Gskj1 effectively enhances the antitumor efficacy of chemotherapy in SCLC, providing compelling evidence for the clinical potential of targeting KDM6B to overcome chemoresistance.

Background: Oral squamous cell carcinoma (OSCC) exhibits poor prognosis due to aggression, metastasis, and chemoresistance. Protein Arginine Methyltransferase 1 (PRMT1) and Signal Transducer and Activator of Transcription 3 (STAT3) are implicated in oncogenesis, but their interplay and downstream effects, particularly concerning ferroptosis and immune evasion in OSCC remain unclear.

Results: PRMT1 was significantly upregulated in OSCC tissues and cell lines, correlating with advanced grade, metastasis, and poor patient survival. PRMT1 knockdown inhibited OSCC proliferation, invasion, metastasis, and chemoresistance in vitro and in vivo. Mechanistically, PRMT1 directly interacted with, methylated, and activated STAT3 (increased p-STAT3 and target genes VEGFA, IL-6, c-myc). The PRMT1/STAT3 axis suppressed ferroptosis; PRMT1 knockdown decreased GPX4 expression, increased Fe2 + , ROS, and MDA, and decreased GSH, effects rescued by STAT3 overexpression. STAT3 directly bound and activated the GPX4 promoter. Crucially, inhibiting ferroptosis with liproxstatin-1 reversed the anti-tumor effects (chemosensitization, reduced proliferation/invasion) of PRMT1 knockdown. PRMT1 KO also enhanced anti-PD-1 therapy efficacy in vivo.

Conclusion: PRMT1 drives OSCC aggressiveness by methylating and activating STAT3. This axis promotes chemoresistance and oncogenic phenotypes primarily by suppressing ferroptosis through STAT3-mediated transcriptional upregulation of GPX4. Targeting PRMT1 represents a promising strategy to overcome chemoresistance and inhibit progression in OSCC.

Background: Increased pulmonary blood flow (IncPBF), one of the most important features of many children with congenital heart diseases, is well-known as a prerequisite for the induction of pulmonary arterial hypertension. However, due to the lack of neonatal mouse models of IncPBF, it remains largely unknown how IncPBF affects postnatal lung development.

Methods and results: A neonatal mouse model of IncPBF was created via abdominal aorta and inferior vena cava fistula microsurgery at postnatal day 7 (P7) and verified by abdominal ultrasound and cardiac ultrasound. Hematoxylin-eosin staining demonstrated that at P14, the number of alveoli was significantly reduced in the IncPBF group compared with the sham group. Immunostaining further confirmed the results, showing that the markers of alveoli type 1 (AT1), alveoli type 2 (AT2), and endothelial cells were significantly reduced in the IncPBF group compared with the sham group. Moreover, RNA-sequencing analysis demonstrated a substantial difference of gene expression profile between IncPBF and sham lungs, and many gene ontology terms or reactome enrichment that are associated with normal alveolar development and pulmonary function, such as angiogenesis, cell migration, and lipid metabolism, were downregulated. Mechanistically, suppression of Mfap5-positive myofibroblasts or Shh-Gli1 signaling could ameliorate IncPBF-induced alveolar hypoplasia.

Conclusions: IncPBF led to alveolar dysplasia during the early developmental stage, and a neonatal mouse model of IncPBF was successfully created. This study introduced a platform for understanding IncPBF-associated pediatric diseases.

Background: The RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1), also known as heterogeneous nuclear ribonucleoprotein I (hnRNP I), mediates gene expression through splicing regulation. Its role in virus infection is undefined.

Results: We show that genetic ablation of PTBP1 renders cell resistant to herpes simplex virus 1 (HSV-1) infection. HSV-1 utilizes 3-O-sulfated heparan sulfate proteoglycans (HSPGs) for attachment and for infection of epithelial cells. We found that knockout of PTBP1 expression resulted in loss of HS3ST3A1 and HS3ST3B1, heparan sulfate glucosaminyl 3-O-sulfotransferase genes for 3-O-sulfation of the heparan sulfate (HS) chains of HSPGs. Each of the HS3ST3A1/HS3ST3B1 genes is composed of 2 exons separated by an extraordinarily long intron whose removal requires PTBP1-associated looping. We found that PTBP1 interacted with the intronic region of HS3ST3A1/HS3ST3B1 pre-mRNAs and modulated their processing to mRNA. The essential role of PTBP1 in functional HS3ST3A1 expression and in HSV-1 infection was demonstrated by ectopic re-expression in the knockout (ko) cells. In addition, we showed that targeting PTBP1 expression by microRNA mimics reduced disease symptoms in a mouse herpetic stromal keratitis (HSK) model.

Conclusions: The results demonstrate that PTBP1 mediates HSV-1 infection of epithelial cells through splicing regulation of HS3ST3A1/HS3ST3B1. These studies provide a new area for novel therapeutic strategies through splicing regulation.

Colorectal cancer (CRC) is a prevalent malignancy, yet the role of lactylation in its progression remains unclear. This study investigates High Mobility Group Box 2 positive tumor epithelial cells (HMGB2⁺Epi), a lactylation-associated subpopulation. By integrating multi-omics data, including proteomics, single-cell, spatial, and bulk transcriptomics, we explored the function of HMGB2⁺Epi in CRC. Elevated lactylation levels in CRC tissues were correlated with poor prognosis. Single-cell analysis identified HMGB2⁺Epi as a central lactylation-enriched subpopulation. Functionally, HMGB2 enhanced the Warburg effect, promoting CRC cell proliferation, migration, and invasion. HMGB2 knockout reduced lactylation levels and inhibited tumor progression. Mechanistically, NFYB directly bound to the HMGB2 promoter, forming the NFYB-HMGB2 axis that drives lactylation and metabolic reprogramming. Cell-cell communication analysis revealed enhanced interactions between HMGB2⁺Epi and fibroblasts, endothelial cells, and T/NK cells. Molecular dynamics and in-vitro assays suggest that BI-2536 downregulates HMGB2 and lactylation in CRC cells. A risk model based on HMGB2⁺Epi outperformed 125 previously published models in independent cohorts. In summary, HMGB2⁺Epi represents a key lactylation-enriched subgroup, with the NFYB-HMGB2 axis driving CRC progression via lactylation. BI-2536 as a tool compound implicating the HMGB2-lactylation axis, and the HMGB2⁺Epi-based risk model provides a novel target for precision CRC therapy.

Rheumatoid arthritis (RA), a systemic autoimmune disorder driven by chronic joint inflammation and progressive tissue damage, is orchestrated by a complex interplay of immune cells and signaling pathways. Among these, the TAM receptor family, comprising Tyro3, Axl, and MerTK, has emerged as a critical regulator of immune homeostasis and inflammatory resolution. Activation of TAM receptors by their cognate ligands helps restore tissue integrity through key mechanisms including the suppression of innate immune cell activation, enhancement of apoptotic cells (ACs) clearance, and promotion of tissue repair. Given these multifaceted roles, the TAM signaling pathway presents a compelling therapeutic target for RA. This review systematically delineates the biological rationale for targeting TAM receptors in RA, explores their potential as diagnostic biomarkers, and evaluates the current landscape of TAM-directed therapeutics. Ultimately, targeting the TAM axis offers a promising avenue to refine clinical management strategies for RA.

The aggressive proliferation and metabolic adaptability of glioma contribute to poor clinical prognosis, necessitating novel targets concurrently reprogram glioma cells toward a neuron-like, less proliferative, and metabolically suppressed state. Here, we identified neuronal differentiation factor CEND1 as a candidate and explored its impact on glioma growth and metabolism. We demonstrated that CEND1 was significantly reduced in high-grade gliomas and inversely correlated with patient survival. Elevated CEND1 in glioma cells induced a neuron-like morphology, accompanied with attenuated proliferation and migration. CEND1 overexpression suppressed tumor growth and prolonged the survival of animal models of intracranial orthotopic tumor formation. Metabolomics and biochemical assays revealed that CEND1 inhibited PDH activity and mitochondrial oxidative phosphorylation, ultimately reducing ATP levels. Mechanistically, CEND1 activated AMPK to induce cell proliferation arrest and enhance metformin sensitivity. Altogether, our findings reveal that CEND1 coordinates neuronal differentiation with mitochondrial energetic metabolic suppression to exert anti-proliferative function in glioma, supporting its role as a potential target for glioma therapy.