Adipokines are bioactive signaling molecules secreted by adipose tissue that play crucial roles in the regulation of energy metabolism and inflammatory responses. With the global rise in obesity and related metabolic disorders, understanding adipokine-mediated regulation has become increasingly important for addressing chronic inflammation and its systemic consequences. However, the adipokine-mediated crosstalk between metabolic dysregulation and inflammatory pathways remains incompletely understood. Beyond classical adipokines, adipose tissue-derived microRNAs (miRNAs) have been identified as novel paracrine and endocrine signaling molecules, capable of modulating distant cellular functions through exosome-mediated transport. These extracellular vesicle-encapsulated miRNAs are increasingly recognized as key regulators in inter-organ communication and disease development. This review summarizes the current understanding of adipokine secretion mechanisms, roles in metabolic and inflammatory regulation, and the dual functions in both metabolic diseases and cancer. Emerging therapeutic strategies focusing on targeting adipokines and the signaling pathways downstream are also discussed, highlighting the translational potential of adipokines as promising biomarkers and therapeutic targets for the prevention and treatment of metabolic diseases and cancer.

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with limited therapeutic options and poor prognosis. Recent advances in high-throughput sequencing and integrative bioinformatics have unraveled the complex molecular landscape of ACC, highlighting critical genomic, epigenomic, transcriptomic, and immune-related alterations. This review synthesizes current evidence to provide a comprehensive overview of the key molecular mechanisms driving ACC pathogenesis. The role of recurrent mutations (e.g., TP53, CTNNB1), dysregulated cell cycle genes (e.g., CDK1, CCNB1, AURKA), non-coding RNAs, and epigenetic modifications in shaping tumor behavior is discussed. Multi-omics integration and systems biology approaches have enabled the identification of robust prognostic gene signatures and protein biomarkers, offering novel tools for risk stratification. Furthermore, the tumor immune microenvironment is examined, with hypoxia, immune suppression, and checkpoint pathways highlighted as emerging targets. Finally, computational drug repositioning strategies that nominate repurposed agents such as IGF1R inhibitors and BCLAF1 modulators for therapeutic intervention are explored. Together, these insights pave the way for precision oncology in ACC, while emphasizing the need for rigorous multi-layered validation and standardized clinical integration to enable real-world translational impact.

F-box and WD repeat domain-containing 7 (FBXW7), a ubiquitinating enzyme, has been verified as a key factor linking to the mechanical overloading and chondrocyte senescence in the pathology of osteoarthritis (OA). Given the lack of deeply mechanism research on the regulation of OA by FBXW7, elucidation of the action mechanism of FBXW7 in OA could provide theoretical basis for the treatment of OA. OA model was established by injuring the anterior cruciate ligament (ACL). Ferrostatin-1 (Fer-1) was applied for analysis of ferroptosis. After overexpressed or silence of FBXW7, cell viability and apoptosis were determined via CCK-8 and TUNEL staining. The intracellular Fe , GSH concentration, ROS levels and mitochondrial membrane potential were assessed by iron determination kit, ELISA, C11-BODIPY/DCFH-DA and JC-1 staining methods. Western blot and RT-qPCR were carried out for determination of ferroptosis-correlated factors (SLC7A11 and GPX4) and ECM-related factors (collagen II (Col II) and ADAMTS5). The interaction between SLC7A11 protein and FBXW7 was detected by immunofluorescence (IF) and immunoprecipitation (IP). Up-regulation of FBXW7, and down-regulation of SLC7A11 and GPX4 were observed in OA groups, compared to that in Control group. Moreover, FBXW7 overexpression significantly hindered cell viability, injured cell morphology, promoted apoptosis and reduced Col II protein level, while Fer-1 treatment blocked the function of FBXW7 overexpression in OA injury. Additionally, silence of FBXW7 showcased the opposite results, meanwhile decreased Fe level, increased GSH release, reduced ROS content, raised mitochondrial membrane potential and elevated SLC7A11 and GPX4 in OA chondrocytes. Furthermore, SLC7A11 and FBXW7 were co-localized in chondrocytes and exhibited protein interaction. The ubiquitination degradation of SLC7A11 was accelerated by FBXW7 in chondrocytes, which was intercepted by MG132 treatment. In vivo experimental results further uncovered the alleviated functions of FBXW7 knockdown in ferroptosis and cartilage damage in OA model. The finding demonstrated that FBXW7 aggravated OA injury and ferroptosis, which might be linked to the ubiquitination degradation of SLC7A11.

To investigate the intervention effect of epigallocatechin gallate (EGCG) on liver fibrosis and its underlying molecular mechanisms.

MLH1 promoter methylation status may serve as an important diagnostic, prognostic, and predictive biomarker in management of mismatch repair (MMR)-deficient cancers. A new commercial assay for detection of MLH1 promoter hyper-methylation (EntroGen), which interrogates regions C and D, was assessed for its performance characteristics. False positive results were obtained in 5/21 non-lesional cases, with signals limited to region C. Three were explained by overloaded reactions. Two unexplained cases were both muscle samples (2/6 muscle samples, one each of skeletal and smooth). The assay was 100 % concordant (52/52) for lesional samples with expected MLH1 promoter methylation status. These included two exceptional cases-one Lynch-associated, and one POLE-mutated endometrial carcinoma; thus expanding the spectrum of extreme cases, and demonstrate neither germline or somatic NGS results completely rule out MLH1 promoter methylation, and vice versa. The POLE/MLH1 carcinoma was notable for molecular features in keeping with POLE dysfunction, accompanied by multiple, additional genetic lesions in the MMR pathway. Exploring the TCGA dataset, 1/8 cases of POLE (ultramutated) endometrial carcinoma was notable for MLH1 silencing. Comprehensive genomic profiling assay was informative, allowing for correlation of MLH1 methylation and POLE genotype results with tumor mutation burden and mutational signature. Taken together, our data highlight the need for integrated approach in endometrial carcinoma biomarker testing, integrating NGS and MLH1 promoter methylation status, the latter of which benefits from assessing both regions C and D. Finding of MLH1 promoter methylation does not rule out either Lynch syndrome or ultramutated (POLE) carcinoma.

Bladder cancer (BCa) is the most common malignancy of the urinary system. Despite advancements in novel targeted therapies and immunotherapy, the majority of patients remain incurable, and disease progression frequently occurs after treatment. Therefore, identifying new therapeutic strategies is crucial. Fatty acids are essential components of cell structure, playing roles in energy storage and serving as signaling molecules. In tumor tissues, due to abnormal blood vessel development, cancer cells primarily rely on de novo fatty acid synthesis to meet the demands of growth and proliferation. Stearoyl-CoA desaturase 1 (SCD1) is a key enzyme, widely recognized as a potential therapeutic target in various cancers. SCD1 promotes the synthesis of cell membranes by converting saturated fatty acids into monounsaturated fatty acids, thus supporting tumor cell growth. In this study, we conducted bioinformatics analysis using public datasets (including bulk RNA-seq and single-cell RNA-seq) and immunohistochemical examination of BCa tissues. Our findings reveal that SCD1 is specifically expressed in BCa cells and is associated with poor tumor grade and prognosis. Furthermore, drug sensitivity predictions and validations suggest that SCD1 enhances the sensitivity of BCa cells to trametinib. Therefore, SCD1 offers a promising new avenue for the early diagnosis, prognostic assessment, and optimization of personalized treatment strategies for BCa.

Chronic diseases like neurodegenerative disorders, musculoskeletal issues, metabolic diseases, cancer, liver and kidney disorders are increasingly linked to mitochondrial dysfunction. PINK1-Parkin-mediated mitophagy, a vital autophagic process, plays a central role in maintaining cellular homeostasis by selectively eliminating damaged mitochondria, which is crucial for preserving mitochondrial integrity and preventing reactive oxygen species accumulation. Activation of the PINK1-Parkin signaling pathway has emerged as a promising therapeutic strategy to restore mitochondrial function and attenuate disease progression. Recent studies have demonstrated that natural PINK1-Parkin activators offer significant therapeutic potential for treating a wide range of chronic diseases by modulating mitochondrial dynamics, alleviating cellular inflammation, and preventing mitochondrial damage. This review provides an in-depth analysis of the molecular mechanisms underlying PINK1-Parkin signaling, discusses the therapeutic benefits of natural activators, and presents them as a compelling strategy for addressing mitochondrial dysfunction and mitigating the progression of chronic diseases.

Diabetic Kidney Disease (DKD) is a significant complication and leading cause of death in both type 1 and type 2 diabetes, as well as the primary cause of chronic kidney disease. Macrophage migration inhibitory factor (MIF) activates the NLRP3 inflammasome. Chicago sky blue 6B (CSB6B) is a MIF inhibitor with therapeutic potential in various inflammatory diseases, but its effect on DKD remains unexplored.

Hypertrophic scar (HS) is a severe fibrotic disease characterized by excessive fibroblast activation and extracellular matrix deposition. While previous studies have revealed the involvement of Aortic Carboxypeptidase Like Protein (ACLP) in other fibrotic diseases, the role of ACLP in HS has not been investigated.

Human epidermal growth factor receptor 2 (HER2) is an emerging therapeutic target in endometrial carcinoma (EC). Current guidelines recommend routine HER2 testing for p53 abnormal (p53abn) tumors, potentially underestimating its value in non-p53abn cases. This study aimed to assess the incidence and clinical relevance of HER2 immunoreactivity in advanced non-p53abn EC.

To investigate the presence and clinical significance of tertiary lymphoid structures (TLSs) in HER2-low breast cancer, by focusing on their associations with clinicopathological features and prognosis.

The predominant cause of mortality in breast cancer patients arises from tumor invasion and metastasis. The tumor microenvironment (TME) plays an indispensable role in breast cancer development and progression. In recent years, intervention strategies targeting TME have become a research hotspot for suppressing breast cancer metastasis. In this review, we summarize a deep insight of therapeutic approaches against cancer by remodeling TME: (1) vascular normalization strategies to inhibit tumor invasion and metastasis by improving the structure and function of the tumor vasculature; (2) targeting cancer-associated fibroblasts (CAFs) aiming to reduce tumor invasiveness by inhibiting the pro-tumorigenic activity of CAFs; (3) targeting senescent cells to reduce the pro-invasive nature of TME by removing senescent cells or modulating their secretion of the senescence-associated secretory phenotypes (SASP); (4) targeting exosomes to inhibit tumor invasion and metastasis by interfering with exosome-mediated intercellular communication and blocking signaling between tumor cells and TME; and (5) targeting cancer-associated adipocytes (CAA) in order to intervene in tumor progression by regulating metabolism and secretion of adipocytes. We summarize TME-remodeling approaches and their recent research progress. These strategies show promising results in breast cancer treatment and may advance precision therapy.

Breast cancer (BC) remains a major cause of cancer-related mortality among women worldwide, with estrogen receptor-positive (ER) tumors representing the most common subtype. Tamoxifen (TMX), a selective estrogen receptor modulator, has been a cornerstone in ER BC therapy for decades. However, its clinical utility is hampered by its high lipophilicity, poor water solubility, systemic toxicity, off-target effects, and the emergence of resistance. In recent years, nanoparticle (NPs)-based drug delivery has emerged as a promising approach to surmount these challenges and enhance the therapeutic potential of TMX. These NPs not only improve solubility and bioavailability but also demonstrate validated outcomes such as resistance reversal, prolonged plasma half-life, significant tumor inhibition, and reduced systemic toxicity, thereby underscoring their clinical-translational potential in BC. This review critically analyzes the limitations of traditional TMX therapy and critically evaluates the role of various NPs-based strategies in overcoming these barriers. Furthermore, we explored the potential of multifunctional NPs to co-deliver TMX with other therapeutic agents to achieve synergistic effects and circumvent resistance. Overall, this review highlights the transformative potential of NPs-enabled TMX delivery systems and provides future perspectives on their clinical translation for better BC management.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder identified by persistent synovial inflammation, joint destruction, and systemic complications. Affecting approximately 0.5-1 % of the global population, RA poses a considerable burden in terms of disability and healthcare costs. Over the past century, insights into RA pathogenesis-driven by immune dysregulation, genetic predisposition, and environmental triggers-have revolutionized therapeutic strategies. This review provides a detailed overview of the evolving landscape of RA drug development, tracing the progression from conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as methotrexate and sulfasalazine, to targeted synthetic DMARDs (tsDMARDs) like JAK inhibitors, and biologic DMARDs (bDMARDs) including TNF and IL-6 antagonists. We explore the molecular underpinnings of RA, discuss the mechanisms of action and clinical applications of current therapies, and highlight emerging drug candidates under clinical investigation. Despite significant advances, challenges such as incomplete remission rates, variable patient responses, and long-term safety concerns underscore the need for precision medicine and novel therapeutic approaches. This review emphasizes the critical role of immunopathology in guiding RA drug development and the ongoing efforts to achieve personalized, sustained disease control.

Vascular calcification (VC) is a pathological process characterized by the deposition of calcium phosphate crystals in blood vessels. Despite its clinical significance, the molecular mechanisms underlying VC remain poorly understood. This study integrated transcriptomic data from public datasets and experimental models to identify key regulators of VC. Human aortic smooth muscle cells (HASMCs) were induced to calcify using osteogenic medium (OM), followed by transcriptomic sequencing. Differential gene expression, functional enrichment, and machine learning-based hub gene identification, were performed. Experimental validation was conducted using in vitro and in vivo models. Transcriptomic analysis identified 278 differentially expressed genes (DEGs), 45 of which were associated with metabolism. Bioinformatic and machine learning approaches highlighted Osteomodulin (OMD), and Stanniocalcin 2 (STC2) as key regulators of VC. The iRegulon tool predicted that OMD and STC2 share a common transcription factor Activating Transcription Factor 4 (ATF4). In calcified human vascular tissues, ATF4, OMD, and STC2 expression levels were significantly upregulated, correlating with increased calcification markers such as RUNX2, ALP, and OCN. Functional studies demonstrated that ATF4 transcriptionally upregulates OMD and STC2 by binding to their promoter regions, then activated the PI3K/AKT signaling pathway, promoting osteogenic differentiation in HASMCs. In vivo experiments using AAV-SM22α-shATF4 confirmed that targeting ATF4 alleviates VC by suppressing OMD and STC2 expression and reducing calcium deposition. In conclusion, our study reveals that ATF4 promotes vascular calcification by transcriptionally upregulating OMD and STC2,which in turn activates the PI3K/AKT signaling pathway. These findings provides new evidence for the direct regulatory relationship between signaling nodes in the field of VC signaling network.

Breast cancer (BC) is the chief cause of malignancy-related deaths in women. This paper investigates how the EBF3-ACADL axis inhibits BC progression through Hippo/YAP signaling.

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality. Microsatellite instability-high (MSI-H) tumors, resulting from defective DNA mismatch repair (MMR), represent a well-defined subtype with distinctive biological behavior and immunogenicity. In contrast, tumors with elevated microsatellite alterations at tetranucleotide repeats (EMAST) are less well characterized. EMAST can manifest with MSI or arise as an isolated form of instability, delineating discrete phenotypes underpinned by distinct mechanisms. This study aimed to characterize MSI and EMAST status in CRCs. By integrating instability profiles with clinicopathological features and mutational profiles of key driver genes, we aimed to refine molecular classification and advance understanding of CRC tumorigenesis. A total of 332 CRCs were analyzed for MSI and EMAST using established panels. Clinicopathological characteristics were recorded, and mutational profiling of KRAS, BRAF, CTNNB1, PIK3CA, and TP53 was performed. MLH1 expression was assessed using immunohistochemistry. MSS/EMAST-S tumors displayed profiles typical of chromosomally stable CRC, dominated by KRAS and followed by TP53 and PIK3CA mutations. MSI-H/EMAST-H tumors were characterized by frequent BRAF mutations, right-sided location, female predominance, and lower TP53 mutation rate, consistent with the classical hypermutated, immunogenic subtype. In contrast, MSS/EMAST-H tumors exhibited unique features, including enrichment for PIK3CA and CTNNB1 mutations, larger tumor size, and poorer differentiation, suggesting an intermediate phenotype between MSS and MSI-H. MSS/EMAST-L tumors aligned with chromosomally stable, KRAS/Wnt-driven CRC. In conclusion, MSS/EMAST-H tumors represent an underrecognized CRC subtype with intermediate genomic instability and a distinctive molecular profile, with potential implications for prognostic assessment and personalized therapeutic strategies.

Drug-resistant epilepsy (DRE) still poses one of the greatest therapeutic challenges, afflicting about one-third of all patients with epilepsy in the world. Despite spectacular advances in the fields of anti-seizure medications and neurostimulation techniques, treatment outcomes in DRE have reached plateau levels, signifying an urgent need for better mechanistic understanding and therapeutic strategies. New evidence increasingly elucidates mitochondrial dysfunction as a lens through which to understand seizure generation, pharmacoresistance, and disease progression. Mitochondria are regulators of ATP production, calcium buffering, and redox homeostasis; disruption of any such pathway will result in neuronal hyperexcitability, oxidative injury, and cell death. Moreover, mitochondrial DNA mutations and heteroplasmy threshold can correlate with seizure onset, seizure severity, and Response to treatment, thus being potential biomarkers for risk stratification. This narrative review surveys both preclinical and clinical evidence for mitochondrial dysfunction in epilepsy, examining oxidative stress pathways, mitophagy, and mitochondrial permeability transition pore opening as key mechanisms of neuronal vulnerability. We subsequently analyze various preclinical models of mitochondrial dysfunction, pointing out their respective strengths and weaknesses. Emerging therapeutic strategies, encompassing pharmacological agents, gene therapy, diet, and natural compounds, are then reviewed, which aim to resolve issues surrounding mitochondrial health on a molecular basis. By straddling the mechanistic and clinical narratives, this work foregrounds mitochondrial-centered approaches as promises for both the diagnostic and therapeutic arsenal in the management of DRE.

Hepatocellular carcinoma (HCC) is a global health challenge with limited treatment options, largely due to the ability of tumor cells to evade programmed cell death (PCD). Dysregulation of key PCD pathways; apoptosis, necroptosis, pyroptosis, and autophagy plays a pivotal role in hepatocarcinogenesis, progression, and therapy resistance.

Differentiating benign from malignant lung tumors remains a critical and often challenging task in histopathological diagnosis. With the advancement of artificial intelligence (AI), large language models such as ChatGPT offer novel opportunities for assisting in diagnostic workflows.

Magnetic resonance imaging (MRI) and dynamic contrast enhancement MRI(DCE-MRI) data of osteosarcoma patients prior to neoadjuvant chemotherapy (NAC) were compared in order to investigate the value of imaging histological features in predicting the rate of tumor necrosis in osteosarcoma and patients' postoperative survival.