👤 Yiqing Jin

Cervical cancer (CC) remains a major global health challenge, with radiotherapy resistance (RR) representing a critical impediment to treatment efficacy. This study investigated the underlying mechanisms of replication stress (RS) in RR and identified potential therapeutic targets for CC. A comprehensive bioinformatics workflow was applied to analyze the expression profiles and prognostic significance of RS-related differentially expressed genes (RSRDs) in patients with RR. The prognostic utility of an RS-based risk score model was subsequently evaluated in the context of the tumor microenvironment, somatic mutation landscape, etc. The clinical relevance of the identified hub RSRDs was validated through immunohistochemistry, univariate and multivariate Cox regression analyses, and a prognostic nomogram using data from a real-world patient cohort. Functional assays conducted both in vitro and in vivo further confirmed the role of the key RSRD. Thus, enrichment analysis of the 124 common differentially expressed genes showed RS-related biological processes were enriched. The RS risk score model, constructed using 2 hub RSRDs (AXIN1 and C-terminal binding protein 1) identified through Least Absolute Shrinkage and Selection Operator (LASSO) regression, showed strong diagnostic and prognostic performance. Enrichment analysis showed the risk score model influenced CC prognosis by tumor microenvironment and mutation, etc. Immunohistochemistry analysis of tissue microarrays explored a significant downregulation of AXIN1 in RR samples. AXIN1 was also an independent prognosis biomarker for CC patients, particularly among patients receiving radiotherapy. Knockdown of AXIN1 significantly inhibited the radiosensitivity in CC cell lines, and in vivo experiments showed AXIN1 knockdown led to increased tumor volume following radiotherapy. Molecular docking analysis illustrated JQ1 may promote AXIN1 expression. This study is the first to identify AXIN1 as a replication stress-associated gene with prognostic value in CC, specifically in the context of radiotherapy. These findings may support personalized treatment strategies and provide a foundation for future investigations into RS-targeted therapies in CC. Show less

Clubfoot, medically termed congenital talipes equinovarus (CTEV), is a prevalent musculoskeletal birth defect, affecting approximately 0.3% of all live births. This serious congenital anomaly results from structural abnormalities in the foot and lower leg, leading to abnormal positioning of the ankle and foot joints. This review provides a comprehensive overview of the causative factors associated with CTEV and evaluates current therapeutic approaches. Although variations in genes encoding contractile proteins of skeletal myofibers have been proposed as contributors to the etiology of CTEV, no definitive candidate genes have been conclusively linked to increased risk. However, genes such as Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying efficacy. Addressing this critical therapeutic gap, natural multi-target compounds like mulberroside A (MsA)-a bioactive glycoside from Show less

To explore the mechanism by which BALB/c mice were infected by intraperitoneal injection with TgCtwh3 wild type (TgCtwh3 WT) and TgCtwh3 Δ BALB/c mice injected with TgCtwh3 Δ Our results indicated that the GRA15 Show less

Phenyl salicylate, an important industrial raw material, is widely used in plastics, cosmetics, and pharmaceuticals. However, little is known about its neurotoxicity on wildlife. Here, we exposed zebrafish embryos at 4 hours post-fertilization (hpf) to 0.025, 0.05, 0.1, 0.25, 0.5, and 1.0 mg/L of phenyl salicylate up to 144 hpf and found its developmental- and neuro-toxicity. Specifically, a dose-dependent increase in mortality and malformation in zebrafish were revealed. Phenyl salicylate also adversely affected the development of monoaminergic neurons, cerebral blood vessels, and the blood-brain barrier (BBB), as well as induced cerebral hemorrhages and locomotion change. RNA-sequencing results combined with verification data showed that phenyl salicylate downregulated the expression of the N-myc downstream regulated gene-1 (ndrg1), caused myelin damage in zebrafish, and then increased expression of beta-secretase 1 (bace1), which ultimately led to early Alzheimer's disease (AD)-like symptoms, including BBB leakage, bleeding in the brain, and upregulation of the glial fibrillary acidic protein gene (gfap) and cholinergic system-related gene (chrna7a). In conclusion, phenyl salicylate exposure triggered developmental toxicity and neurotoxicity in zebrafish, which has a potential risk for the development of AD. Given the effects of phenyl salicylate exposure to ecosystem, the safety usage limit should be treated with caution. Show less

Mitochondrial unfolded protein response (UPR The data were sourced from the cancer genome atlas (TCGA) and GSE31210 dataset and MRGs were retrieved to identify those with prognostic relevance, which were applied to recognize the molecular clusters in LUAD. The cluster-specific differentially expressed genes (DEGs) were identified for the functional enrichment analysis. The independent differentially expressed MRGs were sorted out to develop a risk model. Besides, the tumor immune microenvironment was analyzed using the ESTIMATE, TIMER, MCP-counter, and ssGSEA algorithms. The data were processed with Mutect2 to evaluate the genetic mutation landscape, while the IMvigor210 cohort and pRRophetic package were utilized to predict immunotherapeutic responses and drug sensitivity. Finally, in vitro validation was performed via quantitative real-time PCR (qRT-PCR), cell counting kit-8 (CCK-8), wound healing, and Transwell assays. Most MRGs were higher expressed in LUAD, and CREB binding protein (CREBBP), lysine demethylase 6B (KDM6B) and leucine rich pentatricopeptide repeat containing (LRPPRC) were the top 3 genes with mutation frequency. 8 MRGs were applied to identify 2 molecular clusters, with the worst prognosis seen in cluster C1. The clusters-specific DEGs were mainly enriched in cell proliferation-related pathways and the established risk model based on 4 hub genes (ANLN, FAM83A, CPS1 and KRT6A) showed satisfying efficacy in predicting the prognosis and was negatively correlated with most immune cells. Besides, the tumor mutation burden tended to be stronger in high risk group with high gene mutation frequency. In IMvigor210 cohort, higher RiskScore was seen in patients with progressive disease and stable disease and related to a worse survival. 3 drug candidates, including Roscovitine, Rapamycin and PHA.665752 were positively correlated with RiskScore. Besides, all 4 MRGs were highly expressed in LUAD cells and the silencing of ANLN repressed the LUAD cell proliferation, migration and invasion. The established 4-MRGs signature not only serves as a robust prognostic indicator but also highlights the significant involvement of mitochondrial unfolded protein response in shaping tumor microenvironment and influencing immunotherapy outcomes in LUAD. The 4 MRGs may contribute to the understanding on UPR Show less

Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic (DA) neurons, which may serve as an intrinsic neuroprotective mechanism in Parkinson's disease (PD). LRRK2 G2019S is the most common pathogenic mutation associated with PD. In this study, we explored whether mitochondrial transfer is influenced by genetic and environmental factors and whether dysfunction in this process is one of the mechanisms of the pathogenic LRRK2 G2019S mutation. DA neurons and astrocytes were differentiated from induced pluripotent stem cells generated from the peripheral blood of a healthy individual and a PD patient carrying the LRRK2 G2019S mutation. A coculture system of astrocytes and DA neurons was established to explore the pathogenic mechanisms of LRRK2 G2019S. Exposure to the environmental toxin rotenone impaired mitochondrial transfer from astrocytes to DA neurons. Compared with the co-culture system from the healthy participant, the co-culture system harboring the LRRK2 G2019S mutation experienced more pronounced damage. Specifically, STX17 was colocalized with the mitochondrial outer membrane marker TOM20, and its knockdown caused damage to mitochondrial transfer. Drp1 interacted with STX17. LRRK2 G2019S-mutant astrocytes exhibited markedly increased phosphorylation of Drp1 at Ser616 upon rotenone exposure. Moreover, the degree of colocalization of STX17 with TOM20 decreased. The Drp1 phosphorylation inhibitor DUSP6 restored the colocalization of STX17 and TOM20, as well as the mitochondrial transfer efficiency and neuronal survival. The impairment of mitochondrial transfer is a potential pathogenic mechanism associated with LRRK2 G2019S mutation. The molecular mechanisms of mitochondrial transfer were observed to occur through a Drp1-STX17-dependent pathway. Notably, inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through mitigating mitochondrial transfer impairments. This study provides novel insights into the pathogenesis of PD and the development of new therapeutic targets. Show less

Cervical cancer remains one of the leading causes of cancer-related deaths among women globally, and there is still a need to research molecular targets that can be used for prognosis assessment and personalized molecular therapies. Here, we investigate the role of potential molecular target ribosomal L22-like 1 (RPL22L1) on cervical cancer, identify its potential mechanisms, and explore its related applications in prognosis and molecular therapies. Multiple cervical cancer cohorts online, tissue microarrays and clinical tissue specimens were analyzed for the association between RPL22L1 expression and patient outcomes. Functional and molecular biology studies of cell and mice models were used to clarify the effects and potential mechanisms of RPL22L1 on cervical cancer. RPL22L1 is highly expressed in both cervical adenocarcinoma and squamous cell carcinoma, and its expression is significantly associated with histology grade, clinical stage, recurrence, vascular space involvement, tumor sizes and poor prognosis. In vitro and in vivo experiment revealed that RPL22L1 overexpression significantly promoted cervical cancer cell proliferation, migration, invasion, tumorigenicity and Sorafenib resistance, which were attenuated by RPL22L1 knockdown. Mechanistically, RPL22L1 competitively binds to ERK phosphatase DUSP6, leading to excessive activation of ERK. The combined application of ERK inhibitors can effectively inhibit RPL22L1 overexpressing cervical cancer cells both in vivo and in vitro. RPL22L1 promotes malignant biological behavior of cervical cancer cells by competitively binding with DUSP6, thereby activating the ERK pathway. The combined use of Sorafenib and an ERK inhibitor is a potentially effective molecular targeted therapy for RPL22L1-high cervical cancer. Show less

Observational studies have suggested associations between dietary polyunsaturated fatty acids (PUFAs) and cancer risk; however, causal inference regarding skin cancer remains limited due to potential recall bias, confounding, and reverse causation. This study aimed to evaluate the causal association between genetically predicted circulating PUFA levels and the risk of skin cancers, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. We conducted a 2-sample Mendelian randomization (MR) study using genome-wide association study summary statistics from the UK Biobank (PUFAs, n=115,006) and the FinnGen consortium (BCC, n=26,272; SCC, n=4,663; melanoma, n=5,753). Genetic instruments were derived for omega-3, docosahexaenoic acid, omega-6, linoleic acid, and the omega-6:3 ratio. Multiple MR methods-including inverse-variance weighted, MR-Egger, weighted median, weighted mode, and MR-PRESSO-were applied to test for consistency and assess pleiotropy and heterogeneity. A higher genetically predicted linoleic acid to total fatty acid ratio was associated with a significantly lower risk of BCC and SCC. Conversely, higher genetically proxied serum omega-3 levels were associated with increased risks of BCC, SCC, and melanoma. The risk effect on SCC was attenuated upon exclusion of rs174528, a variant in the fatty acid desaturase 1 ( This MR analysis supports a causal role of circulating PUFAs in skin cancer development and highlights the importance of FADS-mediated endogenous PUFA metabolism. These findings provide novel insights into the genetic and metabolic underpinnings of skin cancer susceptibility. Show less

Observational studies have demonstrated a close association between polyunsaturated fatty acids (PUFAs) and acne. However, the findings of clinical trials have been inconsistent, leaving the causal relationship between PUFAs and acne unclear. To investigate the causal association between genetically proxied PUFAs and acne risk. Mendelian randomization (MR) was performed using single nucleotide polymorphisms associated with PUFAs as instrumental variables. The causal associations between PUFAs and acne were estimated among 115 006 UK Biobank participants and 363 927 participants of Finnish descent. Genetically predicted docosahexaenoic acid (DHA) levels [β = -0.303, 95% confidence interval (CI) -0.480 to -0.126; P = 7.74 × 10-4] and its percentage to total fatty acids (β = -0.402, 95% CI -0.651 to -0.258; P = 5.91 × 10-6) showed a significant causal association with a decreased risk of acne. Conversely, genetically predicted percentages of linoleic acid (LA) in total fatty acids (β = 0.768, 95% CI 0.411-0.126; P = 2.87 × 10-4) and omega-6 : omega-3 ratio (β = 0.373, 95% CI 0.142-0.604; P = 4.48 × 10-3) were robustly associated with an increased risk of acne. These effects were attenuated after excluding a genetic variant of rs174528 located upstream of FADS1, highlighting the biologic link between FADS1 and delta-5 desaturase activity. Multivariable MR analysis indicated that PUFAs were causally associated with acne, independent of body mass index. Our study indicates that high DHA levels and their ratios to total fatty acids have causal protective effects against acne, while high LA levels and omega-6 : omega-3 ratio are associated with increased acne risk. This association was largely attributable to the influence of genetic variants related to FADS1. Show less

Microplastics intrigue kidney toxicity such as mitochondrial dysfunction and inflammation promotion. However, as an organ relying heavily on fatty acid oxidation, how microplastics influence kidney lipidomes remain unclear. Hence, we performed Raman spectra and multidimensional mass spectrometry-based shotgun lipidomics to decode kidney lipidomics landscape under polypropylene microplastics exposure. Kidney functions and cellular redox homeostasis were remarkably disturbed as revealed by levels of biochemical renal function markers, malonaldehyde, hydrogen peroxide and antioxidants. Ultrastructure alterations including the foot process fusion implied the kidney injury associated with lipidomic changes. Raman spectra successfully further confirmed the cellular change of reactive oxygen species and lipid disorders. Lipidomics showed that polypropylene microplastics caused abnormal lipidome and irregular exchange by remodeling triglycerides and phospholipids. Genes involved in lipid metabolism such as Fads1 and Elovl5 exhibited highly diversified expression profiles responding to polypropylene microplastics stress and possessed significant correlations with ROS indicators. These results explained ultrastructure alterations and aggravation of kidney injuries. Our work revealed polypropylene microplastics inducing lipidomic detriment in mouse kidney by Raman spectra and lipidomics firstly, elucidating the significances of lipidomic remodeling coupled with ROS stress in the kidney damages. The findings provided reliable evidence on the health risks of polypropylene microplastics in kidney. Show less

RNA interference (RNAi) holds promise as a gene-silencing therapy for liver cancer but faces challenges related to siRNA instability, short half-life, and inefficient cellular uptake. In this study, we designed a self-assembling RNA nanoparticle targeting three oncogenes- Show less

Podocyte injury is central to diabetic kidney disease (DKD) pathogenesis, however, the mechanisms underlying podocyte loss remain unclear. Emerging evidence underscores the involvement of fibroblast growth factors (FGFs) in renal pathophysiology. Here we reveal a previously unappreciated role of podocyte-secreted FGF4 in safeguarding renal function. FGF4 expression is downregulated in renal tissues from DKD patients and animal models, correlating with disease severity. Podocyte-specific deletion of Fgf4 exacerbated podocyte loss and accelerated DKD progression in mice. Conversely, treatment with recombinant FGF4 (rFGF4) improved glomerular filtration and reduced renal injury and fibrosis in diabetic male mice. These effects are primary mediated by activating the FGFR1-AMPK-FOXO1 signaling cascade in podocytes, which mitigates oxidative stress, suppresses apoptosis, and fosters podocyte survival. Notably, rFGF4 also restores the morphology and function of human podocytes exposed to high glucose. Our findings establish FGF4 as a critical regulator of podocyte homeostasis and a potential therapeutic target for DKD. Show less

Protein arginine methyltransferase 5 (PRMT5) complexes with methylosome protein 50 (MEP50) play crucial roles in tumor progress. However, the regulatory mechanism of governing the PRMT5-MEP50 hetero-octameric complex remains unclear. Here, we demonstrate that C6orf223, to our knowledge an uncharacterized protein, facilitates PRMT5-MEP50 multiprotein complex assembling, thereby promoting colorectal cancer (CRC) growth and metastasis. C6orf223 forms dimers through disulfide bonds, with its N-terminal arginine-enriched region binding to the C-terminal negatively charged groove of PRMT5, thus stabilizing PRMT5-MEP50 multiprotein and enhancing PRMT5 methyltransferase activity. Consequently, PRMT5-mediated H4R3me2s substantially decreases the expression of the tumor suppressor GATA5, leading to the upregulation of multiple oncogenic target genes including WWTR1, FGFR1, and CLU. Targeting C6orf223 using siRNAs encapsulated in ferritin protein shells effectively suppresses CRC tumor growth and metastasis. Collectively, our findings characterize the role of C6orf223 in facilitating PRMT5-MEP50 hetero-octameric complex assembling and suggest that C6orf223 could serve as a potential therapeutic target for CRC. Show less

Ischemic stroke (IS) remains a leading cause of mortality and disability, with limited therapeutic options due to poor drug delivery to ischemic lesions. To address this challenge, an engineered Salmonella based therapeutic method for targeted drug delivery and long-term treatment is herein designed to mitigate ischemic damage. We engineered an attenuated luminescent Salmonella typhimurium (S.t -ΔpG) strain with an L-arabinose-inducible pBAD system to secrete bioactive FGF21. C57BL/6 mice were used to to measure neuron apoptosis and the activity of immune cells following IS induction plus S.t-ΔpG injection. Bioluminescence imaging was applied for bacterial colonization. ELISA and glucose uptake assays were performed to detect FGF21 secretion and the bioactivity. Neurological tests, TTC staining, and TUNEL labeling were used to assess the therapeutic effects of barterially secreted FGF21. Immunofluorescence assay of FGF21/FGFR1 dominant pathway was explored to investigate neuroprotective mechanism, while IBA-1 staining, CD3/CD68 immunostaining, cytokine profiling, and hepatorenal histopathology were detected to evaluate biosecurity. S.t-ΔpG Our study presents a novel, Salmonella - based platform for targeted and sustained FGF21 delivery, offering a promising therapeutic strategy for ischemic stroke with robust efficacy and minimal systemic toxicity. Show less

Pediatric arterial ischemic stroke (AIS) is the leading cause of stroke in children and approximately two-thirds of affected patients experience permanent neurological sequelae. Although basic fibroblast growth factor (bFGF) has positive effects on neural development, axon regeneration, and synaptic reconstruction, its effects in AIS remain unclear. Here, we examined the role of bFGF in post-ischemic cognitive function in juvenile rats. Behavioral assessments using the Morris water maze and the three-chamber test revealed that bFGF knockdown impairs spatial learning, memory, and social interactions. Golgi staining and electron microscopy demonstrated that bFGF knockdown disrupts neuronal axon morphology and synaptic ultrastructure. In the hippocampus of AIS rats, bFGF deficiency significantly reduced PSD95 and synapsin I protein levels. Moreover, bFGF knockdown decreased autophagy and apoptosis markers while increasing necrosis indicators. Mechanistically, loss of bFGF inhibited phosphorylation of mammalian target of rapamycin (mTOR), a process regulated by fibroblast growth factor receptor 1 (FGFR1). We further show that bFGF interacts with FGFR1 and caveolin-1 (Cav1), a membrane scaffold protein; knockdown of Cav1 in the hippocampus similarly attenuated mTOR signaling. Collectively, our results suggest that bFGF deficiency suppresses Cav1, thereby inhibiting mTOR signaling and exacerbating cognitive deficits after AIS in juvenile rats. These findings provide insight into the molecular mechanisms underlying pediatric AIS. Show less

Time-restricted feeding (TRF) is a dietary intervention that has been shown to have numerous health benefits. However, it is important to further investigate the potential effectiveness of TRF in addressing sarcopenic obesity (SO), which is characterized by a combination of age-related obesity and sarcopenia. In this study, 14-month-old C57BL/6J male mice were fed either regular chow diet or high-fat diet (HFD), and had either ad libitum or restricted access to food for 8 hours daily (Intervention for 7 months). For the human trial (ChiCTR2100052876), obese individuals (n=21) with a Body Mass Index ≥28 were recruited and instructed to adopt an 8-hour eating window and a 16-hour fasting period. Here, we found that the TRF intervention significantly reduced global fat mass (P < .001) and volume (P < .05), and increase lean mass compared to mice fed with HFD. Furthermore, TRF improved overall metabolic mobility (8h TRF+HFD vs. AL+HFD). This intervention also enhanced liver FGF21 protein levels (P < .01) and the expression of FGFR1 and FGF21 target genes in adipose and muscle tissues, thus improving mitochondrial quality control in these tissues. Notably, TRF interventions led to a significant decrease in serum FGF21 levels (P < .05). In the human trial, TRF intervention resulted in a significant reduction in weight (P < .001) and body fat levels (P < .001) among obese individuals, as well as a decrease in serum GLU (P < .001), insulin (P < .001), and TC levels (P < .05). Overall, the findings indicate that TRF intervention improves SO by regulating liver FGF21 expression, thereby enhancing FGF21 sensitivity in adipose and muscle tissues. Show less

Schizophrenia is a chronic and severe mental disorder. It is currently treated with antipsychotic drugs (APD). However, APD's work only in a limited number of patients and may have cognition impairing side effects. A growing body of evidence points out the potential involvement of abnormal sphingolipid metabolism in the pathophysiology of schizophrenia. Here, an analysis of human gene polymorphisms and brain gene expression in schizophrenia patients identified an association of SMPD1 and SMPD3 genes coding for acid- (ASM) and neutral sphingomyelinase-2 (NSM). In a rat model of psychosis using amphetamine hypersensitization, we found a locally restricted increase of ASM activity in the prefrontal cortex (PFC). Short-term haloperidol (HAL) treatment reversed behavioral symptoms and the ASM activity. A sphingolipidomic analysis confirmed an altered ceramide metabolism in the PFC during psychosis. Targeting enhanced ASM activity in a psychotic-like state with the ASM inhibitor KARI201 reversed psychotic like behavior and associated changes in the sphingolipidome. While effective HAL treatment led to locomotor decline and cognitive impairments, KARI201 did not. An RNA sequencing analysis of the PFC suggested a dysregulation of numerous schizophrenia related genes including Olig1, Fgfr1, Gpr17, Gna12, Abca2, Sox1, Dpm2, and Rab2a in the rat model of psychosis. HAL and KARI201 antipsychotic effects were associated with targeting expression of other schizophrenia associated genes like Col6a3, Slc22a8, and Bmal1, or Nr2f6a, respectively, but none affecting expression of sphingolipid regulating genes. Our data provide new insight into a potentially pathogenic mechanism of schizophrenia and suggest a new pharmaco-treatment strategy with reduced side effects. Show less

Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells is an important mechanism for the onset and development of broncho-pulmonary dysplasia (BPD). Fibroblast growth factor 2 (FGF2) is involved in the development and repair of injury in many organs, particularly the lung. The role of FGF2 in BPD is currently unclear. The aim of our study was to investigate the expression of FGF2 in lung tissue of BPD mice, to further clarify the effect of FGF2 on EMT in alveolar epithelial cells and to actively search for possible signaling pathways. The BPD model was induced by exposure to hyperoxia. Lung tissue samples were collected and hematoxylin and eosin staining was used to determine the modeling effect. Quantitative real-time polymerase chain reaction (QRT-PCR), immunohistochemistry was used to detect FGF2 expression in BPD mice. To further investigate the effect of FGF2 supplementation and deficiency on EMT in alveolar epithelial cells, A549 cells were cryopreserved, resuspended, cultured, and passaged. Transforming growth factor-β1 (TGF-β1) was used to induce EMT. FGF2 small interfering RNA fragments were synthesized and screened. Fibroblast growth factor receptor 1 (FGFR1) expression was inhibited by BGJ398. (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium) (MTS) assay was used to detect the effect of FGF2 and infigratinib (BGJ398) on cell proliferation. We used qRT-PCR and Western blot to detect the expression of epithelial cell markers, mesenchymal cell markers and EMT-related signaling pathway proteins. Our results showed that the successful established hyperoxia mice model were characteristic by BPD. Hyperoxia decreased FGF2 on day 4, upregulated FGF2 on day 21, which resulted in EMT. In vitro, we found that FGF2 alone increased the expression of mesenchymal markers, decreased the expression of epithelial markers and activated phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), small mother against decapentaplegic (Smad), mitogen-activated protein kinase (P38), and extracellular signal-regulated kinase (ERK) signaling pathways. FGF2 could not reverse but synergistically promote Transforming growth factor-β1 (TGF-β1)-induced EMT of alveolar epithelial cells. Silencing FGF2 increased the expression of epithelial marker E-cadherin, inhibited the PI3K/AKT, Smad, and P38 signaling pathways activated by TGF-β1, but activated ERK signaling. FGF2 receptor inhibitor BGJ398 reversed TGF-β1-induced EMT, decreased the expression of FGFR1, and inhibited ERK signaling pathway activation. FGF2 was closely associated with EMT in BPD mice. Both high and low levels of FGF2 promoted EMT in A549. The FGF2 receptor inhibitor BGJ398 reversed TGF-β1-induced EMT in A549 by inhibiting the FGFR1/P-ERK signaling pathway. Show less

Colorectal cancers (CRCs) are traditionally divided into those with either chromosomal instability (CIN) or microsatellite instability (MSI). By utilizing TCGA data, the Laird team found a subset of CRCs, namely, genome-stable CRCs (GS CRCs), which lack both CIN and MSI. Although the molecular features of GS CRCs have been described in detail, the clinicopathological features are not well defined. A total of 437 CRCs were analyzed for copy number variation (CNV) statuses in eight genes ( Show less

Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure. Conversely, Hey2 depletion in adult mouse hearts and zebrafish enhances the expression of mitochondrial oxidation genes and cardiac function. Multifaceted genome-wide analyses reveal that HEY2 enriches at the promoters of genes known to regulate metabolism (including Ppargc1, Esrra and Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression. Consequently, restoration of PPARGC1A/ESRRA in Hey2- overexpressing zebrafish hearts or human cardiomyocyte-like cells rescues deficits in mitochondrial bioenergetics. Knockdown of Hey2 in adult mouse hearts protects against doxorubicin-induced cardiac dysfunction. These studies reveal an evolutionarily conserved HEY2/HDAC1-Ppargc1/Cpt transcriptional module that controls energy metabolism to preserve cardiac function. Show less

Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, has emerged as a leading cause of mortality in ICU patients. Macrophages, crucial effector cells in innate immunity, play pivotal regulatory roles in sepsis pathogenesis. While Programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, is traditionally believed to exert immunosuppressive effects through membrane anchoring, its involvement in macrophage polarization during sepsis remains unclear. This study investigated the spatial distribution of PD-L1 in macrophages and its regulatory effects on inflammatory responses during sepsis. This study investigated PD-L1’s regulatory role in macrophage polarization through RNA sequencing, Immunoprecipitation-mass spectrometry, molecular docking, and site-directed mutagenesis, with preliminary validation in C57BL/6 mice. Using GEO database analysis combined with qRT-PCR and Western blotting, we confirmed elevated PD-L1 expression in sepsis and M1-polarized macrophages. Laser scanning confocal microscopy demonstrated dual localization of PD-L1, appearing both on the plasma membrane and intracellularly within M1 macrophages. RNA sequencing revealed PD-L1’s promotion of M1 polarization through enhanced AIM2 expression in the NOD-like receptor pathway. Integrated analyses employing mass spectrometry, molecular docking, site-directed mutagenesis, and Western blotting demonstrated PD-L1 binding to AIM2, which augmented expression of downstream effector molecules (IL-18 and IFN-γ) and potentiated STAT1 activation. Silencing AIM2 by siRNA or IL-18 antagonism reversed PD-L1-induced M1 markers (IL-27, IL-6, iNOS/NO). PD-L1 was further shown to exacerbate pathological progression in septic mouse models. Our study demonstrated that sepsis-induced PD-L1 overexpression in macrophages exacerbates pathological progression by upregulating AIM2 expression, binding to AIM2 to enhance IL-18 production, which activates STAT1 to drive M1 polarization. The online version contains supplementary material available at 10.1186/s12964-025-02578-1. Show less

Oxymatrine is an alkaloid with the property of immunomodulation. Recent studies have demonstrated that oxymatrine inhibits experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), by promoting the production of interferon-β (IFN-β). However, the mechanism through which oxymatrine regulates the production of IFN-β remains unclear. The aim of this study was to investigate the pharmacological effects and related molecular mechanisms of oxymatrine in the treatment of EAE through in vivo and in vitro experiments. Oxymatrine alleviated neurological dysfunction, demyelination, and inflammation in EAE mice. It reduced microglia/macrophage infiltration and polarization, lowered pro-inflammatory cytokine levels (iNOS, TNF-α), and enhanced the expression of IL-10 and IL-27. Additionally, oxymatrine upregulated the STING/TBK1/IRF3 signaling pathway in EAE mice, promoting IFN-β production by microglia. Similarly, in LPS-induced BV2 cells, oxymatrine suppressed inflammatory factors and activated the STING/TBK1/IRF3 pathway to enhance IFN-β production. Notably, treatment with the STING inhibitor, C176, reversed these effects in both EAE mice and LPS-induced BV2 cells, confirming the pathway's critical role in the mechanism of oxymatrine therapy. Oxymatrine promotes IFN-β production in microglia by upregulating the STING/TBK1/IRF3 signaling pathway, thereby alleviating the neurological dysfunction of EAE and reducing pathological and inflammatory events. This study identifies a novel anti-EAE mechanism of oxymatrine: promoting IFN-β production in microglia by activating the STING/TBK1/IRF3 pathway. However, it lacks clinical sample verification. If validated later, oxymatrine may provide a more economical, convenient endogenous IFN-β induction regimen for MS patients. Show less

The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-γ production. The mechanisms underlying this functional bias remain elusive. Previous studies have reported that CD4 Show less

Recipients' age has emerged as a key factor that impacts on acute renal allograft rejection and graft survival. Age-related functional and structural changes in the immune system have been observed, yet the precise influence of aged immunity on kidney transplant remains unclear. In an initial retrospective analysis of clinical data gathered from two major centers in China and Germany, we found a correlation between aging and mitigated rejection outcomes in kidney recipients. To study the mechanism, we performed kidney transplantation on mice and observed attenuated allograft rejection in senescent recipients. Single-cell transcriptome analysis of allograft kidneys indicated a protective role of p21 Show less