Bingtao Hao

Aging is the dominant risk factor for retinal neurodegeneration, yet the upstream regulators that coordinate senescence‐associated programs across retinal cell types remain incompletely defined. Here we combined bulk RNA‐seq and quantitative proteomics of retinas from naturally aged (24‐month) and young (4‐month) mice to define age‐associated molecular programs and infer upstream regulators. We identified coordinated but imperfect transcript‐protein coupling, with prominent immune and metabolic activation and concomitant repression of visual and structural pathways. Network‐based integration nominated Stat1 as a convergent hub linking oxidative stress, inflammatory signaling, and cell fate regulation. Functionally, STAT1 induction accompanied oxidative stress‐driven senescence in human ARPE‐19 cells; ectopic STAT1 expression was sufficient to elicit senescence‐like transcriptional changes, increase reactive oxygen species, and activate inflammasome‐associated signaling, whereas STAT1 knockdown attenuated TBHP‐induced senescence, reduced p53 and ASC upregulation, and blocked stress‐induced nuclear accumulation of STAT1. Re‐analysis of aging retina single‐cell RNA‐seq data further localized Stat1 expression primarily to horizontal cells and glial populations, while Stat1 target programs were engaged across multiple retinal cell types, consistent with compartmentalized initiation and multicellular propagation of inflammatory aging cues. Together, these data establish STAT1 as a mechanistic driver and cell‐context‐dependent marker of retinal aging, providing a rationale for targeting STAT1‐centered pathways to delay or mitigate age‐related retinal degeneration.

Down syndrome (DS), caused by trisomy 21, has long been viewed primarily as a neurodevelopmental disorder. However, increasing evidence indicates that it is also associated with pervasive immune dysregulation, including chronic inflammation and heightened susceptibility to autoimmunity. Here, we revisit DS from the perspective of innate immunity and suggest that it shares key features with interferon-driven, autoinflammation-like conditions. Drawing on recent multi-omics studies, we outline a mechanistic framework linking chromosome 21 gene dosage to systemic immune activation. Increased expression of interferon receptors lowers the threshold for signaling and drives persistent activation of interferon-stimulated genes (ISGs). In parallel, reduced METTL3-dependent m ⁶ A modification may stabilize pro-inflammatory transcripts and enhance innate immune sensing. These changes occur alongside chromatin accessibility remodeling enriched for AP-1–associated elements, consistent with a transcriptionally primed state that amplifies inflammatory gene expression. Together, these processes form a feed-forward network involving interferon signaling, transcriptional activation, and cytokine production, providing a basis for the basal inflammatory state in DS and its high burden of immune-mediated comorbidities. This framework also highlights potential therapeutic opportunities, including JAK–STAT inhibition and cytokine-targeted approaches, which may help restore immune homeostasis and inform future translational studies.

Craniofacial development relies on the migration of cranial neural crest cells (CNCCs) to the first and second pharyngeal arches, followed by their differentiation into various cell types during embryogenesis. Although the CNCC migration has been well-studied, the role of the niche in relation to CNCC remains unclear. Variants in FOXI3 have been implicated in craniofacial microsomia (CFM), yet the molecular mechanisms remain unexplored. FOXI3 is expressed in the ectoderm and auricle epidermis, but not in CNCCs or cartilage. Deletion of Foxi3 in the mouse CNCCs did not disrupt mandible and auricular development, further confirming that FOXI3 does not directly regulate CNCCs. However, Foxi3 deficiency in the ectoderm reduced the production of chondrogenesis-related cytokines derived from ectodermal cells, such as TGF-β1. This impairment affected CNCC proliferation through cell communication, subsequently altering the development of the mandible and auricle. These results emphasize the critical role of FOXI3 in establishing the microenvironment supporting CNCC function. Furthermore, FOXI3 directly regulates target genes associated with translation, thereby orchestrating cytokine production in epidermal cells. The validation using auricle sample from a CFM patient carrying FOXI3 mutation further supports our findings. These insights highlight the function of FOXI3 in creating the niche necessary for CNCC development and provide a basis for understanding the molecular mechanisms driving CFM pathogenesis.

Endogenous nitric oxide (NO) produced by nitric oxide synthases (NOSs) plays an important immunosuppressive role in the tumor microenvironment. In melanoma, NOS1 expression increases with tumor progression and correlates with tumor immune escape through the inhibition of type I interferon (IFN) signaling. However, the immune regulatory role and related mechanisms of NOS1, as well as its impacts on immune therapies such as immune checkpoint blockade (ICB) in melanoma, remain unclear. Here, we found that NOS1 expression induces IRF7 modification by S-nitrosylation at the C435 site in mice (C481 in humans), which functionally promoted tumor growth in mouse models. Mechanistically, IRF7-C435-SNO inhibited IFNβ transcription under PRR signal activation, leading to a disorder in the initiation of the type I interferon response in melanoma cells. In a melanoma mouse model, IRF7-C435-SNO decreased the infiltration and activation of CD8 + T cells in the tumor microenvironment by reducing antigen presentation processes in tumor cells and inhibiting the maturation of DC1. Clinically, high expression of NOS1 correlated with poor survival prognosis and resistance to ICB anti-tumor therapies in melanoma cases with less immune cell infiltration. Our study suggests that NOS1 expression in melanoma characterizes IFN-I signal disorders in response to innate immune stimulation through IRF7 s-nitrosylation. Targeting NOS1 signaling might be beneficial for overcoming immune therapeutically resistance, particularly in immune-cold melanoma phenotype.

The iron regulatory protein IREB2 (Iron Responsive Element Binding Protein 2) plays a crucial role in maintaining cellular iron homeostasis through the posttranscriptional regulation of genes involved in iron metabolism. Mutations in the IREB2 gene have been linked to NDCAMA (OMIM#618451), a rare genetic neurological disorder characterized by early-onset neurodegeneration, choreoathetoid movements, and microcytic anemia. However, the absence of an IREB2-mutated animal model has left the underlying pathogenic mechanisms poorly understood. To investigate this, we establish a CRISPR-Cas9-mediated Ireb2^D826V/D826V mouse model, which carries the c.2477A>T (p.D826V) pathogenic variant in IREB2 identified in a Chinese pedigree with NDCAMA. Behavioral studies, including the Morris water maze (MWM), open field test (OFT), and Y-maze, reveal significant neurobehavioral deficits, such as impaired spatial learning and memory and reduced motor activity, in Ireb2^D826V/D826V mice. Furthermore, we observe increased microglial activation and decreased dendritic spine density in the hippocampus, along with impaired long-term potentiation (LTP) and elevated paired-pulse facilitation (PPF), indicating synaptic dysfunction. Mechanistically, Ireb2^D826V/D826V mice present reduced Ireb2 protein levels, dysregulated iron metabolism, and an altered expression profile associated with neurological function. This study elucidates the molecular mechanisms underlying NDCAMA and establishes Ireb2^D826V/D826V mice as a model for iron metabolism-driven neurodegeneration. This finding links the instability of IREB2 to synaptic failure and neuroinflammation, highlighting potential therapeutic implications for neurodegenerative diseases.

Wang and colleagues linked SARS-CoV-2 infection during early pregnancy to situs inversus, a rare developmental anomaly of organ placement. However, the absence of genetic testing data raises concerns regarding the reliability of their conclusions, particularly since a similar association was not observed in Scandinavian countries. In this study, we summarize the cases of situs inversus diagnosed during the COVID-19 pandemic in Henan, China, which indicates a significant increase in the incidence of this condition. Among the 34 cases examined, 24 did not reveal any potential pathogenic variants through genetic testing. Our findings suggest a correlation between SARS-CoV-2 infection and the development of situs inversus.

T cell receptor (TCR) diversity, essential for the recognition of a wide array of antigens, is generated through V(D)J recombination. The Tcra and Tcrd genes reside within a shared genomic locus, with Tcrd rearrangement occurring first in the double-negative (DN) stage during thymocyte development. Elucidating the regulatory mechanisms governing Tcrd rearrangement is therefore crucial for understanding the developmental coordination of both Tcrd and Tcra rearrangements. Chromatin architecture, orchestrated by CTCF-cohesin complexes and their binding sites, plays a fundamental role in regulating V(D)J recombination of antigen receptor genes. In this study, we report that EACBE, a CTCF binding element (CBE) located downstream of the Tcra-Tcrd locus, regulates Tcrd rearrangement. EACBE promotes the usage of proximal V_δ gene segments by facilitating spatial proximity between the Tcrd recombination centre and these V_δ elements. Notably, EACBE counteracts the insulating effects of INTs, two CBEs that demarcate the proximal V region from the D_δ-J_δ-C_δ cluster, thereby enabling effective chromatin extrusion. Furthermore, EACBE indirectly shapes the Tcra repertoire through its influence on Tcrd rearrangement. These findings reveal a novel regulatory axis involving special chromatin configuration and highlight distinct roles for specific CTCF binding sites in modulating antigen receptor gene assembly.

Congenital ptosis, a genetic disorder involving levator palpebrae muscle dysfunction, is often associated with congenital myopathy. The genetic causes of this condition remain poorly understood. In this study, we identified FOXK2 mutations in five pedigrees with congenital myopathy and ptosis through whole exome sequencing and Sanger sequencing. Zebrafish with foxk2 deficiency exhibited underdeveloped skeletal muscles and reduced mobility, while mice with Foxk2 deletion in skeletal muscle stem cells (MuSCs) showed generalized skeletal muscle abnormalities. Further analysis revealed that FOXK2 deficiency impaired myogenic differentiation in C2C12 cells and disrupted mitochondrial homeostasis in both mouse MuSCs and C2C12 cells. Rescue experiments confirmed the loss-of-function effects of FOXK2 mutation. Coenzyme Q10 treatment improved mitochondrial function and alleviated skeletal muscle development defects in Foxk2 -deficient mice. Preliminary omics analysis suggested FOXK2 directly regulates the expression of mitochondrial function-related genes by modulating chromatin accessibility at its binding sites. Our study identifies FOXK2 as a novel pathogenic gene for congenital myopathy with ptosis and highlights its essential role in skeletal muscle development and mitochondrial homeostasis, offering insights for potential diagnostics and therapies.

Corrigendum: Pregnancy outcomes of 4,200 fetuses with increased nuchal translucency in Henan, ChinaZhenglong Guo1*, Wenke Yang1, Qiongrui Zhao1, Yuwei Zhang1, Xin Wang1, Jinming Wang1, Ruili Wang1, 2, Bingtao Hao1*, Shixiu Liao1*1Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics&National Health Commission Key Laboratory of Birth Defects Prevention, Medical Genetics Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China.2Department of Ultrasound, Henan Provincial People's Hospital, Zhengzhou, China.*Correspondence*:Zhenglong Guo, Email: zhenglongguo@zzu.edu.cn.Shixiu Liao, Email: ychslshx@henu.edu.cn.Bingtao Hao, Email: haobt123@163.com.Keywords: nuchal translucency thickness, pregnancy outcome, first-trimester screening, chromosome abnormalities, ultrasound soft indicatorsA Corrigendum onPregnancy outcomes of 4,200 fetuses with increased nuchal translucency in Henan, China by Guo Z, Yang W, Zhao Q, Zhang Y, Wang X, Wang J, Wang R, Hao B and Liao S (2025) Front. Med. 12:1514504. doi: 10.3389/fmed.2025.1514504.Error in TableIn the published article, there was an error in Table 3 as published. There is an error in the statistical values reported in "Cases, NT thickness, and Maternal age". The corrected Table 3 and its caption Pregnancy outcome of 4,200 fetuses with NT ≥ 3.0 mm appear below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.