👤 Feiqi Zhu

Obesity has become a global epidemic and a major contributor to the development of Type 2 diabetes (T2D) through the promotion of insulin resistance. Emerging evidence has shown that GPX4 expression is reduced in macrophages under hyperglycemic conditions; however, the involvement of macrophage-specific GPX4 in obesity-associated insulin resistance remains unclear. We generated macrophage-specific Gpx4 knockout (Gpx4 Show less

Radiotherapy (RT) for breast cancer may increase atrial fibrillation (AF) risk. This study explored the association between RT and expression of AF-related genes in breast tumor tissues. A total of 1094 breast cancer patients (RT group: 1020; non-RT group: 74) were included based on inclusion criteria. Clinical data and RNA-seq profiles (TPM) were retrieved. Six AF-related genes (MYBPC3, LMNA, PKP2, FAM189A2, KDM5B, MYL4) were analyzed. Gene expression was compared using Wilcoxon rank-sum test after Log2(TPM + 1) transformation. Subgroup analyses were conducted by AJCC stage (I–III), laterality (left/right), age (< 65/≥65 years), clinical subtype (Luminal, HER2-positive, Triple-negative), and PAM50 molecular subtype (Basal, Her2, LumA, LumB, Normal). Multivariate linear regression was applied to evaluate RT’s independent effect on gene expression. In tumor tissues, expression levels of MYBPC3, LMNA, and MYL4 were significantly higher in the RT group compared to the non-RT group.Subgroup analysis revealed higher MYBPC3 expression in the RT group specifically in Stage III tumors, but lower expression in left-sided tumors and in patients < 65 years old. LMNA expression was higher in the RT group in Stage III tumors. MYL4 expression was higher in the RT group in Stage II tumors, in both left and right-sided tumors, and in both age groups (< 65 and ≥ 65 years). No significant differences were found across clinical or molecular subtypes for any gene.Multivariate regression confirmed RT as an independent predictor of increased MYL4 expression (β = 0.204), but not for MYBPC3 or LMNA expression. Sensitivity analysis in the 45–65 age subgroup supports the above findings. Based on tumor tissue analysis, breast cancer radiotherapy is associated with altered expression of AF-related genes (particularly MYL4) in tumor tissues, suggesting a potential molecular link worthy of further exploration in relation to atrial fibrillation. These findings warrant future validation in cardiac or circulatory tissues. The online version contains supplementary material available at 10.1007/s12672-026-04468-5. Show less

The formation of subendothelial macrophage-derived foam cells is a key driver of atherogenesis and contributes to the onset and progression of atherosclerosis (AS). The METTL3 gene, a central mediator of N6-methyladenosine (m6A) RNA methylation, serves as a critical regulatory node at the inflammation-metabolism nexus in immune pathophysiology. This study aimed to investigate the METTL3-mediated regulatory mechanisms in subendothelial macrophage-derived foam cells formation and their association with necrosis and the pro-inflammatory properties of AS lesions. METTL3 expression was significantly higher in human carotid artery plaques compared to non-plaques. Macrophages treated with ox-LDL had an upregulated METTL3 expression, while its knockdown reduced lipid accumulation, foam cell formation, and inflammatory responses in macrophages. Myeloid Mettl3 knockout AS mice exhibited attenuated AS lesions. METTL3 knockdown elevated ABCA1, LXR-α, and ZNF771 expression. Gain- and loss-of-function studies demonstrated that METTL3 modulates lipid accumulation and inflammation partly through the ZNF771/LXR-α/ABCA1 axis. YTHDF2 knockdown increased ZNF771 levels, indicating that METTL3 cooperates with YTHDF2 to suppress ZNF771 expression, thereby inhibiting LXR-α transcription. Macrophage METTL3 exacerbates AS by suppressing cholesterol efflux and amplifying inflammation through YTHDF2-mediated downregulation of ZNF771, which attenuates the LXR-α/ABCA1 axis. Our study identifies a novel METTL3-dependent mechanistic link between foam cell pathology and plaque destabilization. Show less

Male infertility affects approximately one in seven couples worldwide. Prenatal cadmium (Cd) exposure has been shown to affect offspring phenotypes and increase susceptibility to diseases later in life. However, the effects of prenatal Cd exposure on multi-generational offspring fertility and the mechanisms remain unknown. A novel murine multi-generational (F1-F3 offspring) male subfertility model induced by prenatal Cd exposure was developed. The levels of testosterone and steroidogenic enzymes were also lower in these offspring's testes. The ubiquitin-dependent degradation of NR4A1, the upstream transcription factor regulating steroidogenic enzymes, was enhanced across generations upon prenatal Cd exposure. After treatment with MG132, an inhibitor of the ubiquitin-proteasome system, the levels of NR4A1 and steroidogenic enzymes were higher in offspring testes with prenatal Cd exposure. Based on the analysis of the UbiBrowser database and testicular global transcriptome, RAPSN was identified as a novel ubiquitin E3 ligase containing the RING-H2_Rapsyn domain that mediates multi-generational testicular NR4A1 ubiquitination. m Show less

To examine the causal association between obesity and osteoarthritis (OA) using an improved definition of obesity, and to identify mediating genes that may link obesity to OA pathogenesis. We analyzed data from the U.S. National Health and Nutrition Examination Survey (NHANES, 2011-2018; n = 8981). Obesity was defined using body mass index (BMI ≥ 30 kg/m²) combined with body fat percentage (BFP ≥ 25 % in men and ≥ 32 % in women). Logistic regression and subgroup analyses were conducted to evaluate associations with OA. Genetic correlation between obesity and OA was estimated using linkage disequilibrium score regression (LDSC). Two-sample Mendelian randomization (MR) was applied to assess causal effects using genome-wide association study (GWAS) summary statistics for BFP and OA. Transcriptome-wide association studies (TWAS) and colocalization analyses were performed to identify candidate genes. Mediation MR was conducted to verify their mediating roles. Obesity defined by BMI combined with BFP was significantly associated with OA (OR = 1.421, 95 %CI: 1.048-1.925, P = 0.025), and was independent of age, race, and various comorbidities. MR analysis confirmed a unidirectional causal effect of obesity on OA (IVW OR = 2.349, 95 %CI: 2.012-2.743, P < 0.001), with no reverse causality detected. TWAS and colocalization identified MAPK3, RBM6, and PRMT6 as potential mediators. Mediation MR confirmed significant effects of MAPK3 (β = 0.991, P = 0.015) and RBM6 (β = 2.740, P < 0.001) in the obesity-OA pathway. Obesity exerts a causal effect on OA, partially mediated by the downregulation of MAPK3 and RBM6. These genes represent potential targets for the prevention and treatment of obesity-related OA. Show less

Colorectal cancer (CRC) is a highly aggressive malignancy prone to liver metastasis, which significantly worsens prognosis of patients. Autophagy supports tumor cell survival by meeting metabolic demands and evading programmed cell death. This study aimed to develop a prognostic risk signature for CRC patients by integrating autophagy- and metastasis-related genes and to investigate its association with the tumor immune microenvironment and implications for immunotherapy. Weighted gene co-expression network analysis (WGCNA) identified candidate genes related to autophagy and liver metastasis. Univariate Cox and LASSO regression analyses were employed to develop a risk signature in the TCGA cohort, which was subsequently validated using an independent GEO cohort. Functional enrichment, immune infiltration, the heterogeneity and dynamics of macrophages and A prognostic risk signature incorporating six biomarkers ( In our study, we developed and validated a novel autophagy- and liver metastasis-associated prognostic signature for CRC. The risk signature effectively predicts alterations in the tumor immune microenvironment, immunotherapy, chemotherapy sensitivity and intercellular communication across different risk groups. Importantly, our findings reveal that autophagy and liver metastasis synergistically foster an immunosuppressive microenvironment, highlighting a potential target for therapeutic intervention. Show less

Thoracic aortic dissection (TAD) is a life-threatening acute vascular condition with high morbidity and mortality. Endothelial cells (ECs) are critical for maintaining vascular homeostasis, yet the role of endothelial-to-mesenchymal transition (EndoMT), a key cell-fate process in vascular development and disease, in TAD remains poorly defined. Furthermore, the functional role of PDK4 (pyruvate dehydrogenase kinase 4) as a driver of this pathological cell-fate transition has not been elucidated. To delineate the mechanistic contribution of EndoMT to TAD, we integrated transcriptomic profiling and immunofluorescence analysis in human aortic specimens and a β-aminopropionitrile-induced murine model. Following the identification of PDK4 as a critical downstream effector of EndoMT signaling via RNA-sequencing and chromatin immunoprecipitation assays, its functional role was validated using conditional EC-specific knockout mice and adeno-associated virus-mediated endothelial gene modulation. Serum samples were collected, and ELISA was used to measure levels of endothelial injury markers for assessing EC-dysfunction. In addition, therapeutic potential was assessed using dichloroacetate, a small-molecule PDK4 inhibitor. A robust activation of the EndoMT gene program was observed in both human TAD specimens and murine aortic tissues, characterized by the loss of endothelial identity and acquisition of mesenchymal traits. Transcriptomic screening pinpointed PDK4 as a critical mediator upregulated during EndoMT. Mechanistically, we demonstrated that the transcription factor Our findings demonstrate that the pathological EndoMT program is activated in ECs by PDK4, which aggravates TAD development in β-aminopropionitrile-induced mouse models, highlighting PDK4 as a promising therapeutic target for TAD. Show less

Defects in mitochondrial energy metabolism in injured tubular epithelial cells (TECs) are a well-recognized hallmark of kidney injury pathogenesis; however, the key target leading to this defect during the acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition remains elusive. Here, we found that during the AKI-to-CKD transition, the increased WW domain containing E3 ubiquitin protein ligase 2 (WWP2) was shuttled to the mitochondria and disabled TEC mitochondrial energy metabolism by ubiquitinating and degrading complex II subunit succinate dehydrogenase complex subunit C (SDHC), leading to oxidative phosphorylation (OXPHOS) disability and aggravated TEC maladaptive repair. Preemptive and late depletion of Wwp2 both ameliorated unilateral ischemia-reperfusion (UIR) injury-induced AKI-to-CKD transition, and tubular-specific Wwp2 depletion resulted in the same protective phenotype. Furthermore, Sdhc knockdown abolished the protective effects of Wwp2 deletion in UIR mice. Conversely, SDHC overexpression attenuated OXPHOS impairment and TEC injury following WWP2 overexpression. Finally, we leveraged high-throughput virtual screening, enzyme activity assays, and binding affinity assays to identify two candidate WWP2 inhibitors. Both inhibitors significantly improved TEC maladaptive repair and deferred the AKI-to-CKD transition. Overall, we identified WWP2 as a critical regulator of mitochondrial OXPHOS integrity in maladaptive repairing TECs and identified two WWP2 inhibitors as potential drug candidates for interrupting the AKI-to-CKD transition. Show less

Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains unclear. Utilizing in vitro fertilization-embryo transfer and surrogacy, we demonstrated that oocytes from androgen-exposed mice (F1) transmitted PCOS-like traits to F2 and F3 generations. Notably, caloric restriction (CR) in F1 or F2 effectively prevented this transmission by restoring disrupted DNA methylation in oocyte genes related to insulin secretion and AMPK signaling pathways. Further detection in adult tissues of offspring revealed dysregulated DNA methylation and expression of those genes (e.g., Adcy3, Gnas, and Srebf1) were reversed by maternal CR. Moreover, similar benefits of CR were observed in aberrant embryonic methylome of women with PCOS. These findings elucidate the essential role of CR in preventing PCOS transmission via methylation reprogramming, emphasizing the importance of preconception metabolic management for women with PCOS. Show less

Perioperative neurocognitive disorder (PND) describes a range of cognitive impairments associated with surgery and anaesthesia, often driven by neuroinflammation. This study explored a novel adult mouse model, in which preoperative subclinical infection, induced by low-dose lipopolysaccharide (LPS) in combination with surgery, led to cognitive dysfunction in adult mice. Adult male C57BL/6J mice were treated with 0.75 mg/kg LPS two hours before undergoing tibial fracture fixation or appendicectomy. Spontaneous activity and anxiety-like behaviours were tested by open field test. Cognitive outcomes were evaluated using the novel object recognition test and morris water maze. Inflammatory markers and synaptic proteins in the hippocampus were analysed through ELISA, RT-qPCR, and Western blot, while proteomics provided deeper insights into molecular changes. We found that preoperative LPS sensitised the immune system, leading to heightened neuroinflammation and microglial activation after surgery. This was accompanied by memory and learning impairments. Key synaptic proteins, including PSD-95, GAP-43, SYN and mature BDNF, were significantly reduced, indicating disrupted synaptic function. Proteomics revealed changes in pathways related to immune responses, synaptic organisation, and energy metabolism, providing a potential molecular basis for these cognitive deficits. This study provided a practical adult mouse model for PND, demonstrating that low-dose LPS followed by surgery induced an inflammatory response, leading to postoperative impairments in learning and memory. Show less

The increasing global aging population presents significant challenges related to cognitive decline, mental health disorders, and social isolation. Martial arts exercise emerges as a multifaceted intervention promoting mental health and cognitive vitality among older adults by integrating physical activity, cognitive engagement, and social interaction. This review synthesizes evidence on the neural mechanisms underlying the benefits of martial arts, highlighting their role in enhancing brain-derived neurotrophic factor (BDNF) expression, neuroplasticity, and neural connectivity, which support improved executive functions, memory, and emotional regulation. Both hard martial arts and soft practices, such as Tai Chi, offer distinct advantages in addressing age-related cognitive and psychosocial challenges. Additionally, martial arts foster strong social support systems, reducing loneliness and enhancing emotional resilience through community engagement and shared achievement. Physical and functional benefits, including improved strength, balance, and cardiovascular health, further contribute to overall well-being. Despite promising results, current studies are limited by heterogeneity in martial arts styles, short intervention durations, and variable methodologies. Future research should focus on long-term, standardized interventions employing advanced neuroimaging and biomarker assessments to better elucidate mechanisms and optimize training protocols. Integrating martial arts into health promotion strategies holds substantial potential for enhancing mental health, cognitive resilience, and quality of life in aging populations. Show less

ASD is a neurodevelopmental disorder with specific core symptoms. Physical activity has been demonstrated to positively influence the pathological mechanisms underlying autism and to alleviate associated symptoms. A comprehensive synthesis was conducted by reviewing and integrating relevant literature. Literature review revealed that the mechanism of physical activity intervention in autism primarily involves modulation through neuronal factors, glial cells, and gut microbiota. Neuronal factors include brain-derived neurotrophic factor, axonal protein families, and neurotransmitters. Additionally, physical activity helps alleviate stereotypical behaviors and internal anxiety in individuals with ASD, reduce obesity and cardiovascular diseases in some patients, and enhance social communication skills. Show less

To investigate the protective effects of secoisolarciresinol digucoside (SDG) on trans fatty acid (TFA)-induced brain inflammatory response and oxidative stress in offspring mice, and to explore the roles of brain-derived neurotrophic factor (BDNF) 28 and tropomyosin receptor kinase B (TrkB) in this process. Female C57BL/6 mice were used in the study. First, pregnant C57BL/6 mice were divided into 5 groups, receiving a normal diet, TFA, low-dose SDG, medium-dose SDG, and high-dose SDG, respectively. After birth, the offspring of the normal diet and TFA groups were subdivided into 2 groups, the normal diet during pregnancy group and the TFA during pregnancy group. The offspring of the low, medium, and high-dose SDG during pregnancy groups were subdivided into 3 groups of low, medium, and high-dose SDG. As a result, the offspring were divided into 13 groups during the lactation period. Only the mother mice were exposed to TFA or SDG intervention. The growth status of the offspring was monitored. After 21 days of lactation, the offspring were sacrificed and the relevant indicators, including pathological changes in the hippocampal region of the brain, levels of tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ), antioxidant levels, and BDNF and TrkB mRNA and protein expression levels, were measured. Maternal TFA exposure and SDG intervention did not result in significant differences in the weight, brain weight, and brain weight coefficient of offspring ( Maternal exposure to a TFA-enriched environment during pregnancy and lactation can induce varying degrees of structural and functional impairment in the brains of offspring and alter the expression levels of BDNF and TrkB proteins in the offspring brain. SDG intervention during TFA exposure exerts protective effects against brain injury in offspring mice, potentially by regulating BDNF and TrkB protein expression to appropriate levels, reactivating BDNF-TrkB downstream signaling pathways, and alleviating inflammatory and oxidative damage. Show less

Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β cells. A BAF60a V278M mutation associated with decreased β cell GSIS function was identified in human donors. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β cells critical for glucose sensing and insulin secretion. Show less

The sea cucumber collagen contains a high content of hydrophobic amino acids, which play essential roles in various bioactivities. A total of 2647 unknown active peptide fragments (2-20 amino acids) were obtained via virtual enzymolysis from 16 known collagen sequences in Apostichopus japonicus. Then, the novel bifunctional hexapeptide (DCDPRL, 717.788 Da) with hypoglycemic and antioxidant activities was identified via molecular docking and pharmacokinetics. DCDPRL revealed strong radical scavenging capacity in vitro with IC Show less

Leptin, a key adipokine regulating energy homeostasis, has been extensively studied for its potential in the management of obesity. However, its therapeutic efficacy is often limited due to leptin resistance. This review synthesizes animal and clinical evidence on leptin's role in obesity, focusing on models such as genetically deficient mice (e.g., ob/ob, db/db), diet-induced obesity mice, and clinical conditions such as congenital leptin deficiency (CLD), leptin receptor deficiency (LRD), lipodystrophy, and common obesity. The mechanisms underlying leptin resistance are summarized, including hyperleptinemia, impaired JAK2-STAT3 signaling, reduced blood-brain barrier permeability, defective autophagy, endoplasmic reticulum stress, inflammation, decreased leptin receptor expression, leptin signaling pathway dysfunction, increased mTOR activity, and peripheral leptin resistance. Due to these leptin receptor and/or post-receptor signaling pathway defects, leptin or its analogs usually fail to produce the expected weight-loss effect in individuals with overweight or obesity, although they remain highly effective in individuals with CLD and lipodystrophy, as well as in ob/ob mice. Alternative strategies, such as melanocortin-4 receptor (MC4R) agonists (e.g., setmelanotide) for LRD treatment, are very promising. Future directions include enhancing leptin sensitization, combining leptin with other drugs, and exploring partial leptin reduction to mitigate compensatory responses during weight loss. The review emphasizes the complexity of leptin resistance and the necessity of targeted approaches in obesity therapy. Show less

Obesity is a global health challenge marked by substantial inter-individual differences in responses to dietary and lifestyle interventions. Traditional weight loss strategies often overlook critical biological variations in genetics, metabolic profiles, and gut microbiota composition, contributing to poor adherence and variable outcomes. Our primary aim is to identify key biological and behavioral effectors relevant to precision medicine for weight control, with a particular focus on nutrition, while also discussing their current and potential integration into digital health platforms. Thus, this review aligns more closely with the identification of influential factors within precision medicine (e.g., genetic, metabolic, and microbiome factors) but also explores how these factors are currently integrated into digital health tools. We synthesize recent advances in nutrigenomics, nutritional metabolomics, and microbiome-informed nutrition, highlighting how tailored dietary strategies-such as high-protein, low-glycemic, polyphenol-enriched, and fiber-based diets-can be aligned with specific genetic variants (e.g., FTO and MC4R), metabolic phenotypes (e.g., insulin resistance), and gut microbiota profiles (e.g., Show less

Dynamic interactions between genetic predispositions and environmental exposures significantly shape the escalating prevalence of childhood obesity. This systematic review synthesizes observational and clinical trial evidence on the gene-environment interplays influencing childhood obesity, highlighting the role of genetic variants and environmental moderators such as dietary habits, physical activity, sleep durations, parental behaviors, socioeconomic status, ethnicity, gender, as well as lifestyle interventions. We conducted an exhaustive search across 5 databases (Medline, PubMed, EMBASE, Web of Science, and Cochrane Library), adhering to PRISMA guidelines. We ultimately included 147 studies that investigated these interplays in diverse populations. Specifically, 83 studies focused on gene-diet interplays, 23 on gene-physical activity, 5 on sedentary behavior, 3 on screen time, 7 on sleep duration, 10 on parental behavior, 4 on socioeconomic status, 16 on gender, 8 on age, 7 on ethnicity, and 13 on the effects of lifestyle interventions. Notably, we meta-analyzed energy expenditure and macronutrient consumption, including carbohydrates, proteins, and fats, as well as the proportion of energy supplied by each nutrient between carriers and noncarriers of the FTO effect allele, revealing that carriers consumed a higher proportion of fat calories, with no other significant differences noted. This review demonstrates that genetic risk variants, particularly in FTO (e.g., rs9939609) and MC4R (e.g., rs17782313), amplify the adverse effects of obesogenic behaviors, offering insights into the intricate pathophysiology of childhood obesity and suggesting the potential for personalized interventions based on genetic profiles. Show less

During the periparturient period, dairy cows experience negative energy balance due to reduced feed intake, leading to adipose tissue breakdown, liver damage, and fat accumulation. This study examined the gut-liver-brain axis to explore the link between fatty liver disease, changes in hypothalamic appetite-related neurons, and microbiome shifts in dairy cows. Thirty cows were monitored, with daily DMI recordings and blood sampling. Postpartum brain, liver, and ileal contents were collected from 10 selected cows, divided into two groups: H-DMI (slight DMI decrease) and L-DMI (severe DMI decrease). The L-DMI group of cows exhibited higher plasma NEFA, BHBA, ALT, and AST levels, along with severe hepatic steatosis and lipid accumulation. Transcriptome sequencing of the hypothalamic arcuate nucleus (ARC) revealed decreased expression of Hypocretin Neuropeptide Precursor (HCRT), orexin-A (OX-A), Orexin Receptor Type 1 (OX1R), and Cannabinoid Receptor 1 (CB1) in the L-DMI group, while Pro-opiomelanocortin (POMC) and Melanocortin 4 Receptor (MC4R) expression increased. Metagenomic analysis of ileal contents showed reduced abundance of Ruminococcus spp. in the L-DMI group, which may be associated with fatty liver disease (FL). Integrated omics analysis showed that increased MC4R expression was correlated with the elevated abundance of bacteria such as Akkermansia glycaniphila, and reduced abundance of species such as Methanobrevubacter thaueri and Ruminococcus spp. Decreased HCRT expression was also linked to Akkermansia glycaniphila. In conclusion, these changes may affect DMI through the OX-A/POMC pathway, with neurological and gut microbiome alterations potentially leading to appetite suppression, negative energy balance, and the development of fatty liver disease. Show less

Communication of gut hormones with the central nervous system is important to regulate systemic glucose homeostasis, but the precise underlying mechanism involved remain little understood. Nesfatin-1, encoded by nucleobindin-2 (NUCB2), a potent anorexigenic peptide hormone, was found to be released from the gastrointestinal tract, but its specific function in this context remains unclear. Herein, we found that gut nesfatin-1 can sense nutrients such as glucose and lipids and subsequently decreases hepatic glucose production. Nesfatin-1 infusion in the small intestine of NUCB2-knockout rats reduced hepatic glucose production via a gut - brain - liver circuit. Mechanistically, NUCB2/nesfatin-1 interacted directly with melanocortin 4 receptor (MC4R) through its H-F-R domain and increased cyclic adenosine monophosphate (cAMP) levels and glucagon-like peptide 1 (GLP-1) secretion in the intestinal epithelium, thus inhibiting hepatic glucose production. The intestinal nesfatin-1 -MC4R-cAMP-GLP-1 pathway and systemic gut-brain communication are required for nesfatin-1 - mediated regulation of liver energy metabolism. These findings reveal a novel mechanism of hepatic glucose production control by gut hormones through the central nervous system. Show less

To investigate the impact of obesity on brain structure and cognition using large neuroimaging and genetic data. Associations between body mass index (BMI), gray matter volume (GMV), whiter matter hyper-intensities (WMH), and fluid intelligence score (FIS) were estimated in 30283 participants from the UK Biobank. Longitudinal data analysis was conducted. Genome-wide association studies were applied to explore the genetic loci associations among BMI, GMV, WMH, and FIS. Mendelian Randomization analyses were applied to further estimate the effects of obesity on changes in the brain and cognition. The observational analysis revealed that BMI was negatively associated with GMV (r = -0.15, p < 1 The phenotypic and genetic association between obesity and aging brain and cognitive decline suggested that weight control could be a promising strategy for slowing the aging brain. Show less

Osteosarcoma demonstrates limited responsiveness to PD-1 blockade, largely due to its immunosuppressive tumor microenvironment (TME). The specific mechanisms by which cancer-associated fibroblasts (CAFs) contribute to immunosuppression in osteosarcoma are not fully understood. We performed single-cell RNA sequencing (scRNA-seq) on osteosarcoma tissues from patients treated with neoadjuvant chemotherapy and anti-PD-1 therapy to investigate the tumor microenvironment. Cellular composition, gene expression programs, and signaling pathways were analyzed. Functional assays, pull-down and PLA-flow binding validation, and in vivo mouse models were used to dissect the mechanisms by which CAF-derived factors influence CD8⁺ T cell function and contribute to immunotherapy response. We identified a subpopulation of CD36⁺ CAFs, characterized by adaptive uptake of oxidized low-density lipoprotein (OxLDL) and activation of the PPARG-FABP4 axis. This metabolic program promoted ANGPTL4 secretion, which bound integrin on CD8⁺ T cells and activated the JAK2-STAT3 pathway, leading to T cell exhaustion and impaired effector function. In vivo, administration of VitE effectively scavenged OxLDL, reprogrammed the TME, enhanced CD8⁺ T cell infiltration, and synergized with PD-1 blockade to improve tumor control. CD36⁺ CAFs drive immunosuppressive metabolic reprogramming via the OxLDL-PPARG-ANGPTL4 axis, promoting CD8⁺ T cell exhaustion and resistance to immunotherapy in osteosarcoma. Targeting this pathway with VitE alleviated CAF-mediated immune suppression and enhanced PD-1 blockade responses in preclinical models, providing a rationale for metabolism-based combinatorial strategies in osteosarcoma. Show less

Glucocorticoids play a pivotal role in tumorigenesis and cancer progression. However, the prognostic significance of glucocorticoid signaling-related genes remains poorly understood, particularly in kidney renal clear cell carcinoma (KIRC). Collected samples indicated KIRC patients exhibited elevated serum glucocorticoid levels compared to healthy donors (P < 0.05). Glucocorticoid signaling-related genes were curated from the MSigDB database. The TCGA-KIRC cohort was utilized for training, while 7 independent public KIRC cohorts and local samples were employed for validation. Through LASSO and random forest analyses, ACADM, ANGPTL4, and NFKB2 were identified and subsequently incorporated into a multivariate Cox regression model. This gene signature emerged as a robust prognostic indicator across multiple cohorts (pooled hazard ratio [HR] = 2.73, 95% confidence interval [CI] = 2.05-3.65). In local samples, KIRC tissues exhibited increased infiltration of NFKB2+ cells and decreased levels of ACADM+ and ANGPTL4+ cells (all P < 0.05). Meta-analyses and spatial transcriptomics revealed a positive association between the signature and CD8+ T cell infiltration. Furthermore, the signature was associated with T cell exhaustion levels and could predict immunotherapeutic responses in both computational simulations and real-world clinical settings (all P < 0.05). In vivo experiments showed that NFKB2 knockdown inhibited tumor growth and the expansion of CD8+PDCD1+ T cells, effects that were reversible with corticosterone treatment (all P < 0.05). Collectively, a glucocorticoid signaling-related gene signature was developed and rigorously validated as a predictive tool for prognosis and immunotherapeutic response in KIRC, offering valuable insights for guiding personalized treatment strategies. Show less

The intact tendon-bone interface (TBI) consists of four histological layers-tendon, fibrocartilage, calcified fibrocartilage, and bone-that gradually merge into each other, making complete structural restoration after injury challenging. Osteoporosis poses a significant risk for rotator cuff tears (RCTs) and re-tears after arthroscopic rotator cuff repair (ARCR). Activating Leptin receptor (Lepr) mediated Stat3 signaling transduction facilitates the transcription of Runx2 and Sox9, respectively, and promotes osteogenesis and chondrogenesis. Sixty-five female Sprague Dawley rats were used. Animal models-ovariectomy (OVX) and rotator cuff tear and repair (RC)-were employed to simulate typical tendon-bone healing and TBI reconstruction under deficient bone-forming capability. And, grip strength, transcriptome, ELISA, histochemistry, and qPCR were performed to reveal the distinct functional recovery between RC and OVX + RC rats, as well as pathophysiologic exhibition in the TBI at 2-week and 8-week. RC rats exhibited better functional recovery during the proliferative phase of TBI reconstruction, i.e., 2-week, compared to OVX + RC rats, while both RC and OVX + RC rats showed a lower grip strength in the upper limbs during the remodeling phase, i.e., 8-week. In RCTs, where adipogenesis was suppressed in RCT healing, the osteoblast-derived Leptin (Lep) and Angiopoietin like 4 (Angptl4), the Lepr ligands, facilitate osteogenesis and chondrogenesis, resulting in an obvious mineralized band in the reconstructed TBI and a transit cartilage band during the proliferative phase in RC rats. In osteoporosis-comorbid RCTs, where osteogenesis was suppressed while adipogenesis was activated, the adipocyte-derived Lep and Angptl4, particularly Angptl4, facilitated Stat3 phosphorylation and nucleus transfer, Sox9 transcription, and chondrogenesis, which was observed in OVX + RC rats and led to excessive cartilage regeneration. This study demonstrated the role of Lep and Angptl4 in TBI reconstruction, via activating Lepr-mediated Stat3-Sox9 and Stat3-Runx2 signaling pathways, differentially regulating osteogenesis and chondrogenesis, and leading to the distinct clinical outcomes post-ARCR in RCTs and osteoporosis-comorbid RCTs. This study provides fundamental support for increasing Angptl4 in situ for chronogenesis in RCTs and lowering Angptl4 to Lep ratio for osteogenesis in RCTs with osteoporosis comorbidity. Show less

The adipocyte-rich tumor microenvironment (TME) is recognized as a key factor in promoting cancer progression. A distinct characteristic of peritumoral adipocytes is their reduced lipid content and the acquisition of a proinflammatory phenotype. However, the underlying mechanisms by which adipocytes rewire metabolism and boost tumor progression in triple-negative breast cancer (TNBC) remain poorly understood. We utilized transcriptomic analysis, bioinformatic analysis, metabolic flux analysis, protein-protein docking, gene and protein expression profiling, in vivo metastasis analysis and breast cancer specimens to explore how adipocytes reprogram tumor metabolism and progression in TNBC. Our findings reveal that Angiopoietin-like 4 (ANGPTL4) exhibits significantly higher expression levels in adipocyte-rich tumor circumstance compared to the symbiotic environment lacking of adipocyte. Furthermore, ANGPTL4 expression in tumor cells is essential for adipocyte-driven glycolysis and metastasis. Interleukin 6 (IL-6), enriched in cancer-associated adipocytes, and lipolysis-derived free fatty acids (FFAs) released from adipocytes, amplify ANGPTL4-mediated glycolysis and metastasis through activation of STAT3 and PPARα pathways in TNBC cells. Additionally, ANGPTL4 interacts with transcription factor KLF4 and enhances KLF4 activity, which further drives glycolysis and metastasis, whereas KLF4 knockdown attenuates migration and glycolysis in TNBC cells. Importantly, Elevated ANGPTL4 and KLF4 expression was observed in metastatic breast cancer specimens compared to non-metastatic cases and was positively correlated with poor prognosis. Collectively, our results uncover a complex metabolic interaction between adipocytes and TNBC cells that promotes tumor aggressiveness. ANGPTL4 emerges as a key mediator in this process, making it a promising therapeutic target to inhibit TNBC progression. Show less

Male germline development is crucial for the proper establishment of spermatogonial stem cell pool and life-long production of spermatozoa, but the full-term developmental profiling of human male germline is not fully understood. Here, by integrating 92,488 human testicular cells spanning from six-week-old embryos to old men, we constructed a comprehensive human male germ cell atlas. Further analysis found that the precursor of undifferentiated spermatogonia underwent regulatory network reconfiguration starting from week 7 post-fertilization, accompanied by WNT6-FZD3/LRP6-JUN/MYC signaling axis. And JUN and MYC were revealed to be candidate core transcription factors that might inhibit spermatogonia differentiation. In addition, the activation of ANGPTL signaling played a role in the maintenance of human spermatogonial stem cells. Finally, by interrogating the scRNA-seq datasets from idiopathic non-obstructive azoospermia (iNOA) patients, we identified several iNOA-dysregulated genes such as CAPN3, FTMT, IZUMO2 and LACE1, which were significantly down-regulated in round spermatids of iNOA patients. Collectively, our work established an atlas of human male germ cell development, revealing the factors that might regulate male germline development and providing iNOA-dysregulated genes for future clinical diagnosis. Show less