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Traditional biomaterial design often prioritizes empirical knowledge over disease mechanisms and pathological dynamics, resulting in imprecise solutions in complex clinical conditions. Age‐related osteoporosis (A‐OP) is a disease associated with aging, characterized by a dysfunctional pathological microenvironment that hinders the osseointegration of conventional titanium implants. To develop a targeted titanium implant for A‐OP, rat single‐cell transcriptomics is integrated with human serum‐derived transcriptome data to investigate dynamic changes in skeletal stem cells (SSCs) during aging, which guided the implant design. These findings reveal that hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) within SSCs interact via a feedback loop: HSCs undergo premature senescence, leading to depletion of HSCs and secondary senescence of MSCs. Senescent MSCs exhibit adipogenic bias, perpetuating the pathological cycle of A‐OP. Using core genes identified in the transcriptome analyses, resveratrol is selected and utilized it and a GelMA‐chitosan hydrogel to decorate titanium implants for localized delivery. In the A‐OP microenvironment, the hydrogel enables sustained responsive release of resveratrol, which reverses MSC senescence and redirects differentiation from adipogenic to osteogenic lineages, thereby breaking the pathological cycle. This multi‐omics‐driven implant design enhances precision and offers a novel methodology for biomaterial development. Senescent mesenchymal stromal cells (MSCs) drive age‐related osteoporosis (A‐OP) via adipogenic bias. Resveratrol, selected from transcriptome‐identified core genes, is delivered locally using GelMA‐chitosan hydrogel‐functionalised titanium implants. In A‐OP microenvironments, the hydrogel enables the sustained release of resveratrol, which reverses MSC senescence and redirects differentiation from the adipogenic to the osteogenic lineage. This breaks the pathological cycle of A‐OP.

Salivary adenoid cystic carcinoma (SACC) is an intractable malignant tumor originates in the secretory glands and frequently metastasizes to the lungs. Hybrid epithelial‐mesenchymal transition (EMT) cells within the tumors are correlated with augmented proliferative capacity and facilitation of lung metastasis. Single‐cell RNA sequencing and spatial transcriptomic sequencing are employed to reveal the hybrid EMT subsets within the vascular fibroblast microenvironment. These hybrid EMT cells exhibit a pro‐tumorigenic impact in vitro. Notably, cadherin 11 (CDH11), a specific marker for hybrid EMT cells, may exert its regulatory role in cellular function by interfering with branched‐chain amino acids (BCAA) metabolism by inhibiting branched‐chain ketoacid dehydrogenase to activate the mammalian target of the rapamycin pathway, thus making it a potential therapeutic target for SACC. Furthermore, celecoxib and its derivatives are specific CDH11 inhibitors that regulate BCAA metabolism, increase reactive oxygen species production, and subsequently activate the cyclic GMP‐AMP synthase‐stimulator of the interferongene pathway (cGAS‐STING). They also inhibit lung metastasis in NOD‐SCID mice in vivo. Overall, these findings suggest a promising treatment strategy that targets hybrid EMT cells to mitigate lung metastasis in SACC. Celecoxib may serve as a promising clinical intervention for the treatment of lung metastases in patients with SACC. The highly expressed CDH11 in hybrid EMT cells may be a potential therapeutic target for SACC. CXB and its derivatives, as specific inhibitors of CDH11, modulate BCAA metabolism, enhance ROS production, and subsequently activate the cGAS‐STING pathway. In vitro, celecoxib and its derivatives inhibit SACC lung metastasis in NOD‐SCID mice.

Oral squamous cell carcinoma (OSCC) stands as a predominant and perilous malignant neoplasm globally, with the majority of cases originating from oral potential malignant disorders (OPMDs). Despite this, effective strategies to impede the progression of OPMDs to OSCC remain elusive. In this study, we established mouse models of oral carcinogenesis via 4‐nitroquinoline 1‐oxide induction, mirroring the sequential transformation from normal oral mucosa to OPMDs, culminating in OSCC development. By intervening during the OPMDs stage, we observed that combining PD1 blockade with photodynamic therapy (PDT) significantly mitigated oral carcinogenesis progression. Single‐cell transcriptomic sequencing unveiled microenvironmental dysregulation occurring predominantly from OPMDs to OSCC stages, fostering a tumor‐promoting milieu characterized by increased Treg proportion, heightened S100A8 expression, and decreased Fib_Igfbp5 (a specific fibroblast subtype) proportion, among others. Notably, intervening with PD1 blockade and PDT during the OPMDs stage hindered the formation of the tumor‐promoting microenvironment, resulting in decreased Treg proportion, reduced S100A8 expression, and increased Fib_Igfbp5 proportion. Moreover, combination therapy elicited a more robust treatment‐associated immune response compared with monotherapy. In essence, our findings present a novel strategy for curtailing the progression of oral carcinogenesis. In oral carcinogenesis, various cell types, including epithelial cells (Epi_Cxcl9) and macrophages (Macro_S100a8), exhibit significant expression of inflammatory‐related cytokines such as S100A8/S100A9. The overexpressed inflammatory cytokines recruit numerous immunosuppressive cell subsets (Tregs, Macro_Cd274, CD8_Tex, etc.). PD1 monoclonal antibody (PD1 mAb) can specifically block the functional inhibition of CD8_Tex by Macro_Cd274, but simultaneously accompanied by an increase in Treg proportion. Photodynamic therapy (PDT) not only directly kills abnormal cells but also reduces the proportion of Treg. Compared with monotherapy, the combination of PD1 mAb and PDT can reshape the microenvironment and induce a stronger therapy‐related inflammatory response, thereby preventing oral carcinogenesis.

Metastasis is the biggest obstacle to esophageal squamous cell carcinoma (ESCC) treatment. Single‐cell RNA sequencing analyses are applied to investigate lung metastatic ESCC cells isolated from pulmonary metastasis mouse model at multiple timepoints to characterize early metastatic microenvironment. A small population of parental KYSE30 cell line (Cluster S) resembling metastasis‐initiating cells (MICs) is identified because they survive and colonize at lung metastatic sites. Differential expression profile comparisons between Cluster S and other subpopulations identified a panel of 7 metastasis‐initiating signature genes (MIS), including CD44 and TACSTD2, to represent MICs in ESCC. Functional studies demonstrated MICs (CD44high) exhibited significantly enhanced cell survival (resistances to oxidative stress and apoptosis), migration, invasion, stemness, and in vivo lung metastasis capabilities, while bioinformatics analyses revealed enhanced organ development, stress responses, and neuron development, potentially remodel early metastasis microenvironment. Meanwhile, early metastasizing cells demonstrate quasi‐epithelial‐mesenchymal phenotype to support both invasion and anchorage. Multiplex immunohistochemistry (mIHC) staining of 4 MISs (CD44, S100A14, RHOD, and TACSTD2) in ESCC clinical samples demonstrated differential MIS expression scores (dMISs) predict lymph node metastasis, overall survival, and risk of carcinothrombosis. CD44, TACSTD2, S100A14, and RHOD act as signatures to represent cancer‐spreading‐initiating cells in esophageal squamous cell carcinoma. These cells acquire both mobile and stational properties that flavor spreading and anchorage. High signature score predicts poor patient clinical outcomes, including worsen overall survival, increased risk of cancer‐spreading in lymph node, and increased risk of blood vessel blockage by spreading cancer cells.

We used 10 × genomics single‐cell transcriptome sequencing technology to reveal the tumor immune microenvironment characteristics of small cell lung cancer (SCLC) in a patient with malignant pleural effusion (MPE). A total of 8008 high‐quality cells were finally obtained for subsequent bioinformatic analysis, which were divided into 10 cell clusters further identified as B cells, T cells, myeloid cells, NK cells, and cancer cells. Such SCLC related genes as NOTCH1, MYC, TSC22D1, SOX4, BLNK, YBX3, VIM, CD8A, CD8B, and KLF6 were expressed in different degrees during differentiation of T and B cells. Different ligands and receptors between T, B and tumor cells almost interact through MHC II, IL‐16, galectin, and APP signaling pathway. We use 10 × genomics single‐cell transcriptome sequencing technology to reveal the tumor immune microenvironment characteristics of small cell lung cancer (SCLC) in malignant pleural effusion (MPE). A total of 8008 high‐quality cells were obtained and divided as B cells, T cells, myeloid cells, NK cells, and cancer cells (a). Such SCLC related genes as NOTCH1, MYC, TSC22D1, SOX4, BLNK, YBX3, VIM, CD8A, CD8B, and KLF6 were expressed in different degrees during differentiation of CD4+ T cells (b), CD8+ T cells (c), and B cells (d). Different ligands and receptors between T, B, and tumor cells almost interact through MHC II (e), IL‐16 (f), galectin (g), and APP (h) signaling pathway.

Glioblastoma (GBM), a prevalent malignant neoplasm within the neuro-oncological domain, has been a subject of considerable scrutiny. Macrophages, serving as the principal immunological constituents, profoundly infiltrate the microenvironment of GBM. However, investigations elucidating the intricate immunological mechanisms governing macrophage involvement in GBM at the single-cell level remain notably limited. We conducted a comprehensive investigation employing single-cell analysis, aiming to redefine the intricate cellular landscape within both the core and peripheral regions of GBM tumors. Our analytical focus extended to the profound study of macrophages, elucidating their roles within the context of oxidative stress, intercellular information exchange, and cellular trajectories concerning GBM and its assorted subpopulations. We pursued the identification of GBM prognostic genes intricately associated with macrophages. Utilizing experimental research to investigate the relevance of MANBA in the context of GBM. Our investigations have illuminated the central role of macrophages in the intricate interplay among various subpopulations within the GBM microenvironment. Notably, we observed a pronounced intensity of oxidative stress responses within macrophages when compared to their GBM counterparts in other subpopulations. Moreover, macrophages orchestrated intricate cellular communication networks, facilitated by the SPP1-CD44 axis, both internally and with neighboring subpopulations. These findings collectively suggest the potential for macrophage polarization from an M1 to an M2 phenotype, contributing to immune suppression within the tumor microenvironment. Furthermore, our exploration unearthed GBM prognostic genes closely associated with macrophages, most notably MANBA and TCF12. Remarkably, MANBA appears to participate in the modulation of neuroimmune functionality by exerting inhibitory effects on M1-polarized macrophages, thereby fostering tumor progression. To bolster these assertions, experimental validations unequivocally affirmed the promotional impact of MANBA on GBM, elucidated through its capacity to curb cell proliferation, invasiveness, and metastatic potential. These revelations represent a pivotal step towards unraveling the intricate immunological mechanisms governing the interactions between macrophages and diverse subpopulations within the GBM milieu. Furthermore, they lay the foundation for the development of an innovative GBM prognostic model, with MANBA at its epicenter, and underscore the potential for novel immunotherapeutic targets in the ongoing pursuit of enhanced treatment modalities for this formidable malignancy.

Breast cancer metastasis is a complex, multi-step process, with high cellular heterogeneity between primary and metastatic breast cancer, and more complex interactions between metastatic cancer cells and other cells in the tumor microenvironment. High-resolution single-cell transcriptome sequencing technology can visualize the heterogeneity of malignant and non-malignant cells in the tumor microenvironment in real time, especially combined with spatial transcriptome analysis, which can directly compare changes between different stages of metastatic samples. Therefore, this study takes single-cell analysis as the first perspective to deeply explore special or rare cell subpopulations related to breast cancer metastasis, systematically summarizes their functions, molecular features, and corresponding treatment strategies, which will contribute to accurately identify, understand, and target tumor metastasis-related driving events, provide a research basis for the mechanistic study of breast cancer metastasis, and provide new clues for its personalized precision treatment.

Erythroid cells, the most prevalent cell type in blood, are one of the earliest products and permeate through the entire process of hematopoietic development in the human body, the oxygen-transporting function of which is crucial for maintaining overall health and life support. Previous investigations into erythrocyte differentiation and development have primarily focused on population-level analyses, lacking the single-cell perspective essential for comprehending the intricate pathways of erythroid maturation, differentiation, and the encompassing cellular heterogeneity. The continuous optimization of single-cell transcriptome sequencing technology, or single-cell RNA sequencing (scRNA-seq), provides a powerful tool for life sciences research, which has a particular superiority in the identification of unprecedented cell subgroups, the analyzing of cellular heterogeneity, and the transcriptomic characteristics of individual cells. Over the past decade, remarkable strides have been taken in the realm of single-cell RNA sequencing technology, profoundly enhancing our understanding of erythroid cells. In this review, we systematically summarize the recent developments in single-cell transcriptome sequencing technology and emphasize their substantial impact on the study of erythroid cells, highlighting their contributions, including the exploration of functional heterogeneity within erythroid populations, the identification of novel erythrocyte subgroups, the tracking of different erythroid lineages, and the unveiling of mechanisms governing erythroid fate decisions. These findings not only invigorate erythroid cell research but also offer new perspectives on the management of diseases related to erythroid cells.

The prognosis for patients with colorectal cancer (CRC) remains worse than expected due to metastasis, recurrence, and resistance to chemotherapy. Colorectal cancer stem cells (CRCSCs) play a vital role in tumor metastasis, recurrence, and chemotherapy resistance. However, there are currently no prognostic markers based on CRCSCs-related genes available for clinical use. In this study, single-cell transcriptome sequencing was employed to distinguish cancer stem cells (CSCs) in the CRC microenvironment and analyze their properties at the single-cell level. Subsequently, data from TCGA and GEO databases were utilized to develop a prognostic risk model for CRCSCs-related genes and validate its diagnostic performance. Additionally, functional enrichment, immune response, and chemotherapeutic drug sensitivity of the relevant genes in the risk model were investigated. Lastly, the key gene RPS17 in the risk model was identified as a potential prognostic marker and therapeutic target for further comprehensive studies. Our findings provide new insights into the prognostic treatment of CRC and offer novel perspectives for a systematic and comprehensive understanding of CRC development.

Epilepsy is a chronic neurological disorder caused by abnormal synchronous discharges of neurons, with ferroptosis and mitochondrial dysfunction implicated in its progression. However, a lack of resolution at the level of specific cell types has obscured critical roles and molecular mechanisms within the epileptic microenvironment. This study integrated single-nucleus RNA sequencing (snRNA-seq) and bulk RNA-seq data from epilepsy and control samples. We performed dimensionality reduction and clustering to identify 13 cell subpopulations, and then assessed the expression of ferroptosis-related genes (FRGs) and mitochondrial-related genes (MRGs) within 7 major cell types. Three machine learning algorithms were further applied to identify key genes in microglia. Subsequent analyses included immune infiltration, pathway enrichment, and drug-target interaction. Molecular docking and molecular dynamics simulations were used to evaluate the potential binding affinity of the predicted drug. In vivo validation included histopathology, mitochondrial electron microscopy, JC-1 staining, and immunohistochemistry (IHC). We identified six key genes ( , and ), which link ferroptosis and mitochondrial dysfunction with a central role for microglia in epilepsy. These genes were associated with immune infiltration, including increased Th1 cell levels and reduced CD8+ T cell abundance. Enrichment analyses implicated these hub genes in orchestrating key epileptogenic processes, including neuroinflammatory pathways, ferroptosis, and interferon response. was upregulated in epileptic rats, and GJA1 exhibited stable binding with bleomycin. Histopathological and mitochondrial assays confirmed the presence of ferroptosis and mitochondrial damage in epilepsy. This study highlights the interplay between ferroptosis and mitochondrial dysfunction in epilepsy, identifying six key microglial genes as high-priority candidates for future mechanistic and therapeutic investigation. Notably,  is implicated in epileptogenesis for the first time. The stable binding between GJA1 and bleomycin offers a novel avenue for epilepsy treatment, warranting further experimental validation.