Konjac glucomannan (KGM) is a natural polysaccharide with unique physicochemical properties. Due to its excellent gel-forming ability, film-forming capacity, biocompatibility, and biodegradability, KGM exhibits wide applications in diverse areas, such as food engineering, medicine, and environmental protection. However, neat KGM-based materials suffer from insufficient mechanical strength and poor environmental stability, necessitating composite material design to overcome these performance bottlenecks. This review systematically summarizes the recent advances in KGM-based functional composites, mainly focusing on the design strategies for high-performance KGM-based composites. Key approaches include molecular modification, multi-component compounding, and structural design, along with their mechanisms in regulating material properties. Additionally, the latest application progress in various fields is discussed. This review provides valuable insights for the development of high-performance KGM-based functional materials.

Recent evidence establishes the brain metastatic microenvironment as a key regulator of metastatic outgrowth, with oligodendrocytes being established as essential components of the brain metastatic microenvironment. Nonetheless, the mechanisms underlying oligodendrocyte-mediated brain metastasis in lung cancer await clarification. Using orthogonal experimental models spanning clinical specimens and animal models, we investigated the presence and functional roles of oligodendrocytes in lung cancer brain metastasis (LCBM). Combinatorial approaches including scRNA-seq, functional genomics, and mechanistic studies revealed ERBB3 as the critical paracrine factor mediating oligodendrocyte-tumor crosstalk. Through comprehensive analysis, we demonstrated the infiltration of oligodendrocytes in the metastatic niche of LCBM. Functional assays demonstrated that oligodendrocytes significantly enhanced the proliferation, migration, and invasion of brain metastatic cells of lung cancer. Mechanistically, oligodendrocyte-secreted ERBB3 acts as a copper chaperone that competitively mobilizes extracellular copper ions through high-affinity binding to SLC31A1 on tumor cells, thereby promoting intracellular copper accumulation. Additionally, elevated ERBB3 expression in LCBM clinical specimens correlated with significantly reduced overall survival and targeted ERBB3 suppressed lung cancer brain metastasis. Our findings establish oligodendrocyte-derived ERBB3 as a critical mediator of intercellular copper transfer via SLC31A1 binding, which coordinately drives brain metastasis progression. Therapeutic targeting of this copper signaling axis represents a promising strategy against LCBM.

BACKGROUND:B-cell lymphoma 2 (BCL-2) is overexpressed in certain solid tumors (including neuroblastoma), representing a promising target. Venetoclax is a first-in-class, oral, highly selective BCL-2 inhibitor. We report safety, pharmacokinetics, and efficacy of venetoclax in children and young adults with relapsed/refractory solid tumors. PROCEDURE:M13-833 (NCT03236857) was a Phase 1, open-label, global, two-part study. Patients received age-/weight-adjusted venetoclax (400 or 800 mg/day adult equivalent dose [AED]) continuously or intermittently (Days 1-10 of 21-day cycles) as monotherapy or with cyclophosphamide and topotecan (Cy-Topo; Cy 250 mg/m2/day + Topo 0.75 mg/m2/day; intravenously Days 1-5) and myeloid growth factor support. Primary objectives included safety and pharmacokinetic assessments of venetoclax; secondary objectives included efficacy. RESULTS:Fifty-nine patients in the neuroblastoma (n = 36; median age: 8 years [range: 1-17]) and solid tumor cohorts (n = 23; median age: 16 years [range: 3-24]) were assessed. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 35/36 (97%) and 21/23 (91%) neuroblastoma and solid tumor patients, respectively; febrile neutropenia was the most common serious TEAE (neuroblastoma 69%; solid tumors 57%). TEAEs leading to discontinuation of venetoclax occurred in 17% (neuroblastoma) and 9% (solid tumors) of patients. No events of tumor lysis syndrome were observed. Peak venetoclax concentrations (Tmax) occurred 4-6 h post-dose; exposure was comparable across age/weight subgroups. Objective response rates were 31% (neuroblastoma) and 22% (solid tumors). CONCLUSIONS:Recommended Phase 2 dose of venetoclax was 800 mg/day AED (Days 1-10 of 21-day cycles). Venetoclax combined with Cy-Topo chemotherapy had a predictable safety profile and showed modest clinical activity in these cohorts.

BACKGROUND:Breast cancer continues to pose a significant global health burden, accounting for a substantial proportion of cancer-related mortality in women worldwide. Despite advancements in therapeutic strategies, overall survival rates remain suboptimal, underscoring the critical need for innovative prognostic tools to improve patient outcomes. METHODS:In this study, we introduced a novel tumor mitochondria transfer (TMT) scoring system based on 17 core genes to assess mitochondrial dynamics and their potential impact on the tumor microenvironment. Utilizing comprehensive datasets from TCGA-BRCA and GEO databases, we investigated the association between TMT scores and immune-metabolic features at both multi-cell and single-cell resolutions. Single-cell RNA sequencing (scRNA-seq) profiles were used to delineate the biological consequences of mitochondrial transfer. Additionally, co-culture experiments were conducted to validate our findings. RESULTS:Our analysis revealed that elevated TMT scores are strongly associated with adverse clinical outcomes in patients with breast cancer. Tumors with high TMT scores exhibited pronounced hypoxia, immune suppression, and metabolic reprogramming. Specifically, these tumors demonstrated impaired T-cell functionality and enhanced mitochondrial transfer to tumor cells, suggesting a pivotal role for mitochondrial dynamics in promoting immune evasion and metabolic adaptations that drive tumor progression. CONCLUSIONS:The TMT score may represent a novel prognostic biomarker in breast cancer, highlighting the intricate relationship between mitochondrial transfer and tumor pathophysiology. Our findings suggested that targeting mitochondrial dynamics could be a potential therapeutic avenue for exploration, which might enhance breast cancer management strategies. Further exploration of the mitochondrial mechanisms in cancer biology may pave the way for more precise and effective therapeutic interventions.

Background: Capsular contracture is driven by self-amplifying foreign body response (FBR) where inflammatory and fibrotic signals from fibroblasts and macrophages reinforce each other. We hypothesized that cogradient simultaneous blockade of NF-κB as an inflammatory node and TGF-β/Smad as fibrotic node could attenuate the FBR. Emodin has dual inhibitory activity but suffers from poor delivery. Methods: Emodin liposomes (Emo-Lip) were characterized and tested on TGF-β1-stimulated NIH/3T3 fibroblasts and LPS-stimulated RAW264.7 macrophages. In a rat silicone implant model, periprosthetic injections were given for four weeks. Fibrous capsule formation was evaluated by histology, immunofluorescence, and FAPI-PET/CT. Transcriptomic analyses were performed to verify and predict relevant pathways. Results: Emo-Lip had uniform size and high encapsulation efficiency. In vitro, Emo-Lip inhibited fibroblast migration, ROS production, myofibroblast differentiation (α-SMA+) as well as Ctgf expression, while suppressing M1 polarization and reduced IL-12/IL-6 secretion in macrophages. In vivo, Emo-Lip reduced capsule thickness, collagen area, and α-SMA/Col I expression, comparable to dexamethasone. Transcriptomics showed coordinated downregulation of inflammatory/fibrotic genes, and Western blot confirmed suppressed phosphorylation of Smad3. Conclusions: Coordinated two-node blockade of NF-κB and TGF-β/Smad by liposomal emodin reprograms the FBR and effectively prevents capsular contracture in rats, offering a translational strategy for implant-associated fibrosis.

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.

Brain metastases represent a prevalent and lethal complication in advanced lung cancer, where the brain microenvironment is pivotal in facilitating metastatic tumor progression. Recent findings indicate the presence of oligodendrocyte infiltration within lung cancer brain metastases (LCBM). Lipid metabolic reprogramming has emerged as a critical feature of the brain metastatic niche, influencing both tumor cell survival and immune cell function. This study aimed to determine whether oligodendrocytes undergo lipid metabolic reprogramming in LCBM and whether their derived fatty acids functionally promote tumor proliferation and immune modulation. Single cell RNA sequencing (ScRNA-seq), spatial transcriptome sequencing, lipidomics, and lipid tracing techniques to comprehensively analyze metabolic alterations in oligodendrocytes and their dynamic interactions with tumor and immune cells. Western blotting, qPCR and multiple immunofluorescence staining were used to detect the expression of fatty acid synthesis enzymes in oligodendrocytes and immunosuppressive markers in macrophages. Analysis of independent scRNA-seq datasets revealed markedly increased lipid synthesis activity in oligodendrocytes within LCBM. Hypoxic conditions and co-culture with metastatic lung cancer cells further enhanced the expression of fatty acid synthases in oligodendrocytes. Spatial transcriptomics and scRNA-seq indicated that tumor cells and macrophages were major recipients of oligodendrocyte-derived fatty acids, exhibiting enhanced uptake and degradation. Treatment with oligodendrocyte-conditioned medium significantly increased the expression of fatty acid uptake proteins in tumor cells and macrophages. Furthermore, oligodendrocyte-derived fatty acids supported tumor cell proliferation and polarized macrophages toward an immunosuppressive phenotype. Notably, scRNA-seq identified a macrophage subpopulation (Mac_FABP4) as a candidate mediator of lipid-driven immune suppression. These findings delineate the pivotal role of oligodendrocytes in LCBM, revealing their contribution of lipids that enhance tumor proliferation and induce immunosuppression, thereby suggesting that glial lipid metabolism may represent a potential therapeutic target warranting further investigation.

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates that arise within the tumor microenvironment and orchestrate local immune responses. While TLSs have been associated with favorable prognosis and enhanced immunotherapy efficacy in various solid tumors, their heterogeneity, spatial organization, and functional significance in brain metastases from lung adenocarcinoma (LUAD-BrM) remain poorly understood. We retrospectively analyzed 283 surgically resected LUAD-BrM specimens. TLSs were identified on H E and classified by serial IHC into immature (E-TLS) and mature subtypes (PFL-TLS/SFL-TLS). Multiplex IHC incorporating follicular network and vascular-stromal markers (including CD35, CD31, and COL1A1) was used for spatial validation. Survival was assessed using Kaplan-Meier and multivariable Cox models. Patients were stratified into TLS-negative (n = 200), immature TLS (n = 43), and mature TLS (n = 40) groups. Spatial mapping revealed that mature TLS subtypes were more frequently intratumoral, whereas early TLSs were relatively enriched at peritumoral regions. Clinically, mature TLSs were associated with significantly prolonged survival (median PFS: 14.8 vs. 9.9 vs. 6.3 months; median OS: not reached vs. 13.3 vs. 10.2 months; all P < 0.001) and remained an independent favorable prognostic factor. Multiplex IHC profiling demonstrated that mature TLSs were associated with an immune-activated niche characterized by higher CD8⁺ infiltration, reduced PD-1⁺CD8⁺ exhaustion-like features, and decreased immunosuppressive macrophage and PD-L1-associated signals. Single-slide spatial mIHC further validated mature TLS architecture, demonstrating stronger B/T compartmentalization, prominent follicular network features, and enriched vascular-stromal contextualization compared with immature TLSs. TLSs in LUAD brain metastases exhibit marked heterogeneity in maturation and spatial distribution, which stratifies immune contexture and patient outcomes. Mature, intratumoral TLSs define an immune-permissive niche and are associated with significantly improved survival. Collectively, these results highlight TLS maturity as a clinically actionable feature for risk stratification and may inform future TLS-guided precision immunotherapy approaches in LUAD-BrM.

Ocular neovascular disease, characterized by aberrant angiogenesis in the eye, is a primary cause of global vision impairment and blindness. As the primary barrier exposed to hypoxia-related blood metabolites, endothelial cells (ECs) undergo metabolic reprogramming that drives pathological angiogenesis. However, the epigenetic mechanisms that link EC metabolic dysfunction to retinal vasculopathy remain elusive. Methods:Using western blotting and immunofluorescence analysis of retinal sections/whole-mounts, we confirmed increased histone 3 lactylation at lysine 18 (H3K18la). We subsequently identified downstream target genes through integrated CUT&Tag and RNA sequencing (RNA-seq), assessed their angiogenic regulatory functions using siRNA, and validated the mechanisms in vivo employing adeno-associated virus (AAV)-based gene transfer. Results:Our data indicated that histone lactylation levels were elevated in retinal vascular ECs under hypoxic conditions both in vivo and in vitro. In oxygen-induced retinopathy (OIR) retinal vascular ECs, H3K18la was the most prominent modification. Pharmacological inhibition of glycolysis suppressed H3K18la levels, concurrently abrogating EC activation and neovascularization. Combined CUT&Tag and RNA-seq analyses revealed that ETS1 was a direct transcriptional target governed by H3K18la in retinal ECs. Silencing ETS1 substantially inhibited hypoxia-induced proliferation, migration, sprouting, and tube formation in human retinal microvascular endothelial cells (HRMECs). Crucially, in vivo rescue experiments confirmed that ETS1 overexpression reversed the suppression of pathological neovascularization in OIR mice treated with AAV-Pfkfb3-RNAi. Conclusions:Collectively, this study revealed a lactate-driven epigenetic cascade wherein H3K18la licenses ETS1-dependent pathological angiogenesis, providing a promising therapeutic avenue for ischemic retinal diseases.

The treatment of central nervous system (CNS) diseases faces huge challenges, mainly due to the blood–brain barrier (BBB) restricting drug delivery, which leads to many potential treatment methods being unable to effectively reach the target area. In recent years, nasal administration has received extensive attention as a non-invasive drug delivery route because of its anatomical connection with the brain, enabling direct delivery to brain tissue. In particular, the siRNA delivery system based on nanocarriers has shown great promise in the treatment of CNS diseases due to its unique advantages in targeting gene silencing. This article reviews the latest research progress on nasal administration of siRNA nanocarriers, with a focus on the design strategies, administration mechanisms, in vivo and in vitro effects, and safety evaluations of different nanocarriers. The aim is to provide a systematic theoretical basis and future research directions for the application of siRNA nasal administration in the treatment of CNS diseases (see the abstract of the picture).

Osteosarcoma represents the most prevalent primary malignant bone tumor in adolescents and young adults, with limited improvement in survival outcomes observed over recent decades. The development of personalized therapies remains challenging due to substantial molecular heterogeneity and the absence of robust prognostic models. In this study, we developed a machine learning-based consensus prognostic signature (MLPS) by integrating multi-cohort transcriptomic datasets and applying ten distinct machine learning algorithms. The resulting MLPS, comprising 11 prognostic genes, reliably stratified patients into high- and low-risk groups with significantly different survival outcomes and outperformed existing models (C-index = 0.862). The application of functional enrichment analyses revealed immune activation and inflammatory signaling in the low-risk group, consistent with a "hot tumor" phenotype. In contrast, the high-risk group exhibited upregulation of proliferative oncogenic pathways. Of particular significance is the observation that MLPS was able to suggest differential responses to chemotherapy and immunotherapy, thereby under-scoring its clinical utility. Single-cell analysis revealed that LGR4 expression is largely confined to malignant cell clusters. In vitro LGR4 knockdown significantly reduced osteosarcoma cell proliferation, migration, and PI3K-AKT-mTOR pathway activity, confirming its oncogenic role. These findings demonstrate the value of MLPS as a robust tool for prognostic assessment and individualized therapeutic decision-making in osteosarcoma.

Microtia is one of the most common congenital craniofacial malformations, characterized by the maldevelopment of the external and middle ear. While numerous genes have been implicated in syndromic forms of microtia, the genetic underpinnings of isolated microtia remain poorly understood. In this study, we conducted whole exome sequencing (WES) on 201 pedigrees with isolated microtia to investigate its genetic basis. Bioinformatics analysis identified 1362 deleterious variants corresponding to 332 candidate genes, including 40 previously associated with microtia-related phenotypes. Among these, variants in FOXI3, the most frequently identified pathogenic gene for isolated microtia so far, were detected. Remarkably, the remaining 39 genes, which have been recognized as pathogenic in syndromes with microtia, are also suggested to play a role in isolated microtia. However, the precise molecular mechanisms by which these genes contribute to microtia remain to be elucidated. Furthermore, through protein-protein interaction network analysis, functional annotation, and zebrafish expression profiling, we identified two novel genes, MCM2 and BDNF, as the most promising contributors to the pathogenesis of isolated microtia. Our findings, based on the largest WES study of isolated microtia pedigrees to date, provide new insights into the genetic architecture of isolated microtia and suggest promising avenues for future research.

ObjectiveThis study aims to identify potential biomarkers for Hepatoblastoma (HB) using bioinformatics and machine learning, and to explore their underlying mechanisms of action.MethodsWe analyzed the datasets GSE131329 and GSE133039 to perform differential gene expression analysis. Single-sample gene set enrichment analysis (ssGSEA) and weighted gene co-expression network analysis (WGCNA) were utilized to identify gene modules linked to gene set activity. Protein-protein interaction (PPI) networks were constructed to identify hub genes, while random forest and support vector machine models were employed to screen for key diagnostic genes. Survival and immune infiltration analyses were conducted to assess the prognostic significance of these genes. Additionally, the expression levels, biological functions, and mechanisms of action of the selected genes were validated in HB cells through relevant experimental assays.ResultsWe identified 1,377 and 1,216 differentially expressed genes in datasets GSE131329 and GSE133039, respectively. ssGSEA and WGCNA analyses identified 234 genes significantly linked to gene set activity. PPI analysis identified 20 core Hub genes. Machine learning highlighted three key diagnostic genes: CDK1, CCNA2, and MAD2L1. Studies have demonstrated that MAD2L1 is significantly overexpressed in HB and is associated with prognosis. WGCNA revealed that MAD2L1 is enriched in gene sets related to E2F_ TARGETS and G2M_CHECKPOINT. Experimental assays demonstrated that MAD2L1 knockdown significantly inhibits the proliferation, migration, and invasion of HB cell lines, and that MAD2L1 promotes cell cycle progression through the regulation of E2F.ConclusionOur study identifies MAD2L1 as a novel potential biomarker for HB, providing new strategies for early diagnosis and targeted therapy in HB.

BACKGROUND:Osteoarthritis (OA) is a chronic degenerative disorder marked by progressive degradation of articular cartilage. Inflammation and impairment of autophagy are crucial in OA pathogenesis, leading to chondrocyte dysfunction and disease progression. The therapeutic potential of CORM-3, a carbon monoxide-releasing molecule with anti-inflammatory and autophagy-enhancing properties, remains unexplored in OA. METHODS:Chondrocytes were treated with interleukin-1β (IL-1β) to establish an inflammatory model in vitro. The impact of CORM-3 on chondrocyte inflammation, extracellular matrix (ECM) metabolism, and autophagy activity was assessed by RT-qPCR, Western blot, immunofluorescence, and autophagy flow assay. OA was induced in mice to investigate CORM-3's therapeutic potential in vivo through surgical destabilization of the medial meniscus (DMM). RESULTS:CORM-3 significantly inhibited the inflammation of chondrocytes and the imbalance of extracellular matrix (ECM) metabolism induced by IL-1β, thereby exerting a chondroprotective effect in vitro. Mechanistically, CORM-3 effectively inhibited the mitogen-activated protein kinase (MAPK) and mTOR signaling pathways. Further, CORM-3 exerted a similar chondroprotective effect with MAPK-IN-1, a MAPK pathway inhibitor, and rapamycin, a specific mTOR inhibitor. Additionally, CORM-3 also restored the impairment of autophagy. Furthermore, 3-Methyladenine (3-MA), an autophagy inhibitor, reversed CORM-3's chondroprotective effect. In vivo, treatment with CORM-3 inhibited cartilage OA-like lesions to mitigate OA progression. CONCLUSION:This study identifies that CORM-3 inhibits inflammation, maintains ECM metabolism homeostasis, and restores impaired autophagy via inhibiting the MAPK and mTOR pathways, thereby protecting chondrocytes. In vivo, CORM-3 treatment significantly alleviates OA progression, suggesting its therapeutic potential for OA.

Neuroblastoma, an aggressive pediatric malignancy, exhibits aberrant expression of transcription factors implicated in tumor progression. Here, we investigated the functional role of transcription factor 4 (TCF4) in neuroblastoma, focusing on its impact on cellular proliferation and ferroptosis-a regulated form of iron-dependent cell death, and elucidated the underlying molecular mechanism. Firstly, the expressions of TCF4 in neuroblastoma tissues and cell lines were analyzed, and the expressions of TCF4 mRNA and protein were significantly up-regulated. Functional analysis demonstrated that sh-TCF4 could significantly proliferate neuroblastoma cells, which was measured by CCK-8 kit, EdU staining, and clone formation experiments. Concurrently, TCF4 knockdown significantly elevated ROS accumulation and lipid peroxidation levels. Besides, sh-TCF4 decreased the levels of FTH1 and increased the TFR1 expression. Mechanistically, bioinformatic analysis using the JASPAR database predicted TCF4 binding sites within GPX4 promoter, a key ferroptosis regulator. ChIP and dual-luciferase reporter assays confirmed direct TCF4 occupancy and transcriptional activation of GPX4. Rescue experiments further validated the axis, as GPX4 overexpression abrogated the anti-proliferative and pro-ferroptotic effects induced by sh-TCF4. Collectively, the findings revealed TCF4 as a critical promoter of neuroblastoma growth and ferroptosis resistance, acting through direct up-regulation of GPX4. Targeting the TCF4-GPX4 axis may offer a novel therapeutic strategy to enhance ferroptosis sensitivity in neuroblastoma, warranting further preclinical exploration.

Treacher Collins syndrome (TCS) is a congenital disorder primarily caused by the mutation in the Treacle Ribosome Biogenesis Factor 1 (TCOF1) gene. However, the significance of many TCOF1 mutations remains uncertain. We report two novel mutations identified in two TCS families and assess their pathogenicity alongside two previously reported mutations. Both novel mutations, c.2115dupG (p.T706DfsTer52) and c.2142+23_2142+52 del (p.A715VfsTer31), result in truncated proteins lacking nuclear location signals (NLSs), which impedes their entry into the nucleus and reduces mRNA expression level. Notably, the mutation c.2142+23_2142+52 del, leading to the retention of a 62 bp intron and disrupting RNA splicing, represents the first documented case of intron retention in TCS patients. Additionally, the previously reported mutation c.136 C> G (p.L46V) hinders protein nuclear location, while mutation c.1719del (p.N574TfsTer22) significantly decreases mRNA levels. Our research expands the spectrum of TCOF1 mutations and provides evidence clarifying their pathogenic nature. These findings are crucial for genetic counseling and prenatal diagnosis for TCS patients.

BackgroundHepatoblastoma (HB) is the most common malignant liver tumor in children. The expression of TAF9 is frequently upregulated in HB; however, its underlying molecular mechanisms are not yet fully understood, and its potential as a therapeutic target warrants further investigation.MethodsBioinformatic analysis was performed using sequencing datas to evaluate clinical diagnostic and prognostic values of molecules. Biological functions were assessed using in vitro and in vivo experiments. Various techniques, including quantitative PCR, western blotting, immunohistochemistry, RNA immunoprecipitation, RNA pull-down, immunofluorescence, and luciferase reporter assays, were used to investigate the underlying molecular mechanisms.ResultsTAF9 was significantly overexpressed in HB tissues and correlated with poor prognosis. Both lncRNA938 and TAF9 promoted HB proliferation and metastasis. Mechanistically, lncRNA938 directly bound TAF9 and regulated its nuclear localization, while TAF9 activated TTK transcription via promoter binding. TTK inhibitors effectively reversed the epithelial-mesenchymal transition and malignant phenotypes induced by TAF9 overexpression.ConclusionThe lncRNA938-TAF9-TTK axis is a critical driver of HB progression. Targeting this axis, particularly through TTK inhibition, represents a novel therapeutic strategy against HB.

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.

BACKGROUND:Brain metastasis, a leading cause of death in patients with lung adenocarcinoma (LUAD), arises from tumor cells adapting to the unique microenvironment of the brain through metabolic remodeling regulated by key oncogenes. Here, we aimed to determine the role of high mobility group protein box 3 (HMGB3) in regulating tumor cell metabolism to promote the progression and brain metastasis of LUAD. METHODS:A LUAD cell model predisposed to brain metastasis was established, followed by differential gene expression analysis. HMGB3 expression was quantified via single-cell RNA sequencing (scRNA-seq) and immunohistochemistry, with clinical relevance assessed in two retrospective cohorts: the primary LUAD and the LUAD brain metastasis cohorts. Gene enrichment analysis of scRNA-seq and bulk RNA-seq data, along with Western blotting, were performed to identify HMGB3-associated pathways. Co-immunoprecipitation combined with mass spectrometry was used to detect HMGB3-interacting proteins. Gain-of-function, loss-of-function and rescue experiments targeting HMGB3 downstream pathways were conducted in vitro and in vivo. RESULTS:HMGB3 expression was significantly elevated in both primary LUAD lesions and brain metastatic foci, and its upregulation was strongly associated with poor prognosis in LUAD patients, as well as in those with concomitant brain metastasis. HMGB3 enhanced the migration, invasion, and epithelial-mesenchymal transition (EMT) capabilities of LUAD cells in vitro and promoted the development of brain metastasis in vivo. Mechanistically, HMGB3 recruited and interacted with single-stranded DNA-binding protein 1 (SSBP1), inducing its nuclear translocation and reprogramming mitochondrial metabolism. This process elevated cytoplasmic reactive oxygen species levels, which subsequently activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K-Akt) signaling pathway through downregulating phosphatase and tensin homolog (PTEN), ultimately promoting tumor cell proliferation, migration, invasion, and EMT. CONCLUSIONS:This study demonstrated HMGB3 as a key regulator of the brain metastasis of LUAD, orchestrating tumor cells' metabolic adaptation to the brain microenvironment through modulation of mitochondrial metabolism, thereby offering potential therapeutic targets for LUAD brain metastases.