Search Results (431)

The purpose of our study was to assess if spinacetin (SPC), a flavonoid found in spinach, can alleviate the cyclophosphamide (CYP)-induced changes in cystometric and inflammatory parameters indicative of the development of hemorrhagic cystitis. The animal experiments were conducted in female Wistar rats. The cohort of 60 animals was grouped as follows: I—control, II—CYP group, III—SPC group, and IV—CYP + SPC group. The cystometry and biochemical analyses were performed after a fortnight of SPC administration. SPC was found to restore normal cystometric parameters in CYP-induced cystitis and, similarly, it normalized c-Fos expression changes in the central micturition regions. SPC further prevented a massive increase in the bladder wall thickness/permeability due to exposition to CYP administration. CYP instillation resulted in the elevation of biomarkers found in urine (brain-derived neurotrophic factor, BDNF, and nerve growth factor, NGF), and in the bladder detrusor muscle (Rho kinase and vesicular acetylcholine transporter, VAChT), which were successfully restored after administration of SPC. As for the biomarkers in the bladder urothelium, the CYP-induced increases in TNF-α, IL-1β, IL-6, calcitonin gene-related peptide (CGRP), malondialdehyde, 3-nitrotyrosine, insulin-like growth factor-binding protein 3 (IGFBP-3), occludin, organic cation transporter 3 (OCT-3), orosomucoid-1 (ORM1), pituitary adenylate cyclase receptor 1 (PAC1), synaptosomal-associated protein 23 (SNAP23), SNAP25, and synaptic vesicle glycoprotein (SV2A) levels were attenuated by SPC. Finally, CYP administration resulted in a decrease in the heparin-binding EGF-like growth factor (HB-EGF), hemopexin (HPX), T-H protein, and tight junction protein (Z01), and we noted the successful restoration of all these changes in concentrations after application of SPC. In summary, SPC robustly mitigated cyclophosphamide (CYP)-induced cystometric dysfunction and biochemical alterations characteristic of iatrogenic hemorrhagic cystitis. These findings position SPC as a compelling therapeutic candidate and warrant further translational investigation for the management of CYP-induced bladder injury. Full article

The senescence-associated secretory phenotype (SASP) is a hallmark of senescent cells and plays a critical role in the development and progression of various age-related diseases, including cancer, cardiovascular disorders, and neurodegenerative diseases. In this study, we characterize SASP heterogeneity using single-cell RNA sequencing (scRNA-seq) data, focusing on the transcriptional signatures associated with elevated expression of individual SASP genes in mature senescent cells, as well as time-dependent variation in SASP expression across the early and mature senescent states in the WI-38 human lung fibroblast cell line. We generated multiple gene sets, each representing the transcriptional landscape linked to high expression of a specific SASP gene, and integrated them into an ensemble that reflects the temporal dynamics of SASP gene expression. Applying SASP scores derived from this ensemble of gene sets (SASP scores/EGS) to publicly available scRNA-seq datasets from human lung, skin, and eye tissues enabled the identification of senescent fibroblasts and revealed IGFBP7 as a consistently upregulated marker in p21⁺ or p16⁺ fibroblasts across diverse human tissues. Our framework supports improved detection of both early and mature fibroblast replicative senescent cells, offering valuable insights into aging and age-related disease research. Full article

Ochratoxin A (OTA), a prevalent food contaminant, is closely linked to the development of various cancers, including clear cell renal cell carcinoma (ccRCC). However, the potential mechanisms remain to be explored. In this study, we employed network toxicology, machine learning, and molecular docking techniques to systematically investigate the potential molecular mechanisms underlying OTA-associated ccRCC. We normalized transcriptional data from two Gene Expression Omnibus (GEO) datasets and analyzed it using differential expression analysis and weighted gene co-expression network analysis (WGCNA), identifying 3224 ccRCC-associated target genes. These were intersected with 232 predicted OTA target genes, yielding a total of 56 overlapping targets. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that these targets were primarily enriched in critical biological processes, including extracellular matrix remodeling, immune microenvironment regulation, signaling pathway transduction, cellular metabolism, and protein homeostasis. Machine learning analysis identified “glmBoost + RF” (a sequential combination of feature selection and classifier) as the optimal model, from which nine key genes were extracted. SHapley Additive exPlanations (SHAP) analysis revealed five core genes (IGFBP3, ITGA5, PYGL, SLC22A8, LTB4R), with IGFBP3 and ITGA5 serving as the principal driver genes of the model. Validation of the model’s diagnostic efficacy and single-cell transcriptome analysis indicated that the core genes exhibited significant differential expression patterns, cell-type-specific expression characteristics, and high independent diagnostic efficacy. Molecular docking analyses predicted stable interactions between OTA and the core target proteins. These findings suggest potential molecular links between OTA exposure and ccRCC, providing a foundation for hypothesis generation and future experimental validation. Full article

Background: The progression of idiopathic pulmonary fibrosis (IPF) involves distal airway remodeling and bronchiolization; however, the mechanisms driving these changes, particularly the contributions of epithelial stem cells, are not fully understood. K13⁺ hillock cells, normally quiescent in proximal airways, were examined for their potential contribution to IPF pathogenesis. Methods: Spatial immunofluorescence was used to profile K13 expression along the airway axes in IPF and control lungs. Multiplex staining complemented by ex vivo culture assays was used to test expression stability. Single-cell RNA-sequencing (scRNA-seq) data were re-analyzed to identify cell subclusters and pathway enrichments. Meanwhile, cell–cell communication was inferred by using CellChat. Results: K13 was ectopically upregulated in IPF honeycomb cysts, triggering a proximal-like pseudostratified phenotype. This shift was marked by surges in K13⁺ regionally overlapping expression patterns (K5⁺, ~9%; CC10⁺, ~53%; ACE-TUB⁺, ~44%; MUC5AC⁺, ~23%) and a decline in SOX2 expression (~95% to ~64%), with ~70% of residual SOX2^low cells exhibiting elevated K13. Accompanying the expansion of K13⁺ subclusters (basal: 1.8% to 41.5%; club: 10.7% to 31.5%), it was observed that the profibrotic markers (K17, S100A2, LGALS7, IGFBP6) and ontologies related to RNA processing, stress response, and senescence were also enriched. These subclusters also amplified pro-fibrotic signaling (e.g., TGF-β, SEMA3, and GALECTIN-9) associated with epithelial subtypes and HAS1^high fibroblasts. Conclusions: Here, we demonstrate that K13⁺ cell activation is a pivotal event, driving the dysregulated proximalization of distal airways in IPF through fate reprogramming and epithelial-mesenchymal crosstalk. Thus, elucidating these K13-mediated fate dynamics provides a critical framework for understanding IPF pathogenesis. Full article

Objective: Emphysema is an important chronic obstructive pulmonary disease (COPD) phenotype characterized by the destruction of air spaces distal to the terminal bronchiole. Aiming to detect potential emphysema biomarkers and to assess the systemic effects of emphysema in blood plasma, we conducted a small cross-sectional shotgun proteomics study. Methods: This study included N = 40 participants divided into four subgroups (N = 10 per group): patients with emphysema and COPD (CE), patients with COPD but without emphysema (CN), healthy smokers (HS) and healthy never-smokers (HN). The participants were sampled non-probabilistically to be similar in terms of age, sex and comorbidities. Participants’ blood plasma was analyzed using liquid chromatography–mass spectrometry. Bioinformatic analysis included detection of differentially expressed proteins (DEPs) and overrepresentation analysis (ORA). Results: Across all groups, a total of 994 proteins were identified, with NADP-dependent malic enzyme (NADP-ME; encoded by ME1) being the only DEP in the CE vs. CN contrast. Proteins such as BMP1, ADAMTSL-2, -4 and IGFBP4, -5, 6 were identified to be upregulated in CE vs. HN. Fibulin-1, -3 and several immunoglobulin components were identified to be downregulated in the CE vs. HN contrast. ORA revealed several enriched processes, including serine-type endopeptidase activity, insulin-like growth factor I and II binding, and signaling receptor binding. Conclusion: We propose NADP-ME, an important enzyme of intermediary metabolism and redox homeostasis, as a potential biomarker candidate of emphysema. Notably, NADP-ME is also implicated in anoikis resistance. Additionally, changes in the expression levels of BMP1, ADAMTSL-2 and -4, and fibulin suggest potential major systemic effects of extracellular matrix perturbation. As all data was derived from LC-MS analysis, these findings need to be further evaluated with complementary methods. Full article

Pathological cardiac hypertrophy, a major contributor to heart failure, is characterized by an abnormal increase in the size of atria and ventricles. In the context of ventricular hypertrophy, the right ventricle (RV) exhibits less resistance to hypertrophy than the left one (LV). Insulin-like growth factors (IGF-1 and IGF-2) are critical for cell growth and provide cardioprotective effects. Pregnancy-associated plasma protein-A (PAPP-A) is a protease that cleaves insulin-like growth factor-binding protein-4 (IGFBP-4) and enhances IGF bioavailability. This study investigated PAPP-A-mediated IGFBP-4 proteolysis—one possible mechanism of IGF release regulation in rat models of right ventricular (RVH) and left ventricular (LVH) hypertrophy. RVH was induced with monocrotaline, and LVH via renovascular hypertension (1 Kidney 1 Clip (1K1C) model). Systolic blood pressure was measured using tail-cuff plethysmography. Heart morphometry was used to assess the mass of cardiac chambers. Cardiomyocyte purity was confirmed via troponin I immunocytochemistry. Plasma natriuretic type-B peptide (BNP) and C-terminal IGFBP-4 (CT-IGFBP-4) concentrations were quantified by fluoroimmunoassay. RVH and LVH were successfully modelled, with 1.6-fold and 1.3-fold increases in RV (p < 0.0001) and LV masses (p < 0.05), respectively. Plasma BNP was 2–3 times higher in LVH versus control rats. Hypertrophied cardiomyocytes secreted significantly more BNP than controls, showing 3.3-fold and 4.1-fold increases in LVH and RVH, respectively. PAPP-A-mediated IGFBP-4 proteolysis was 4-fold higher in RVH compared to control, but unaffected in LVH. These findings suggest that PAPP-A-specific elevation of IGFBP-4 proteolysis occurs predominantly in RVH, suggesting a differential IGF bioavailability in both ventricles and highlighting PAPP-A as a potential target to increase RVH resistance to hypertrophy. Full article

Periodontitis is a chronic infectious disease characterized by the destruction of the tooth-supporting tissues, including the gingiva, periodontal ligament, and alveolar bone, which may ultimately lead to tooth loss. However, blood-based biomarkers reflecting systemic inflammation in periodontitis remain poorly defined. We analyzed plasma proteomic data from the UK Biobank using Olink Explore proteomics to identify systemic protein signatures distinguishing chronic periodontitis patients (n = 90) from healthy controls (n = 2234). Among 2151 proteins passing quality control, 29 proteins showed significant differential expression (FDR < 1.0 × 10⁻⁵). Growth differentiation factor 15 (GDF15) exhibited the strongest upregulation (mean NPX: −0.183 to 0.157, effect size = 0.337, FDR = 2.82 × 10⁻¹²), followed by N-terminal pro-B-type natriuretic peptide (NT-proBNP) (effect size = 0.594), Interleukin-6 (IL-6) (effect size = 0.450), and Insulin-like growth factor binding protein-(4IGFBP4) (effect size = 0.269). Multiple TNF receptor superfamily members (TNFRSF1A/1B, TNFRSF10A/10B) and proteins involved in extracellular matrix remodeling (COL6A3, ADAM12) and vascular stress (ADM) were significantly elevated. In contrast, EGFR and DNER showed decreased expression. Protein–protein interaction network analysis revealed IL-6 as a central hub protein forming a tightly interconnected cluster with TNF receptor family members. These findings indicate systemic plasma protein profiles associated with chronic periodontitis within this population-based cohort. The identified proteins may provide a basis for future evaluation of blood-based biomarkers for chronic periodontitis, pending further validation. Full article

Background: Sirtuin 3 (SIRT3), a mitochondrial NAD⁺-dependent deacetylase, plays a central role in regulating mitochondrial metabolism, oxidative stress, and cell survival. Although SIRT3 has been implicated in angiogenesis, apoptosis, and inflammation, its global proteomic impact on the brain remains unclear. This study aimed to systematically characterize alterations in angiogenesis-, apoptosis-, chemokine-, and cytokine-related proteins in the brains of SIRT3 knockout (SIRT3 KO aka SIRT3⁻/⁻) mice compared with wild-type (WT) controls. Methods: Adult male C57BL/6 WT and SIRT3 KO mice were analyzed using proteome profiler antibody microarrays covering 53 angiogenesis factors, 21 apoptosis markers, 28 chemokines, and 111 cytokines. Protein expression changes were quantified by chemiluminescence imaging and densitometric analysis. Results: The results showed a distinct suppression of angiogenic proteins (amphiregulin, angiogenin, DPPIV, GM-CSF, IGFBP-2, IGFBP-3, IL-1β, PDGF-AA, PDGF-BB, proliferin, serpin F1, thrombospeondin-2, TIMP-4, and VEGF-B), activation of both pro-apoptotic (BAD, cytochrome c, Smac/DIABLO, HIF-1α, Fas, TNF R1, and TRAILR2) and anti-apoptotic, stress-related proteins (Bcl-x, catalase, HO/HMOX2, HSP27, HSP70, and MCL1) in the SIRT3 KO animals compared with the WT controls. Notably, SIRT3 deficiency was associated with increased expression of inflammatory mediators linked to glial activation and neurodegeneration (BLC/CCL13, LIX/CXCL5, MIG/CXCL9, chitinase 3-like 1, CCL22/MDC, IL-6, myeloperoxidase, osteopontin, RBP4, Reg3G, and TNF-α), alongside disturbed proteins involved in immune surveillance and vascular remodeling (6Ckine/CCL21, chemerin, DF, EGF, fractalkine/CX3CL1, HGF, IGFBP-6, IL-16, and I-TAC). Conclusions: Collectively, these findings demonstrate that SIRT3 is a key regulator of mitochondrial-dependent vascular, apoptotic, and neuroimmune pathways in the brain, and that its loss creates a molecular environment consistent with heightened vulnerability to neurodegenerative processes. Full article

Background: The individual and social burden of endometriosis is high, and the diagnosis is usually delayed by 7–10 years. Menstrual effluent (ME) represents an accessible and uniquely informative biofluid. This systematic review evaluated the pathophysiological relevance and diagnostic potential of ME in endometriosis. Methods: Following PRISMA 2020 guidelines, we systematically searched PubMed/MEDLINE, EBSCOhost (Academic Search Premier, APA PsycArticles, APA PsycInfo, CINAHL, and MEDLINE), Semantic Scholar, and Google Scholar from inception to 30 November 2025. Original studies analyzing human ME or ME-derived cells in women with endometriosis versus controls were eligible. We extracted study design, analytic methods, diagnostic accuracy metrics (AUC, sensitivity, and specificity), mechanistic pathways, and risk of bias (QUADAS-2 for diagnostic, and NIH tools for mechanistic studies). Results: Thirty-five studies were included. ME consistently captured key pathophysiological mechanisms of endometriosis, including impaired decidualization and progesterone resistance, immune dysregulation with diminished cytotoxic clearance, pro-angiogenic and invasive phenotypes, heightened stem/progenitor cell survival, cellular senescence and DNA damage, and altered extracellular-vesicle signaling. Diagnostic accuracy was reported in nine studies. Aromatase mRNA showed the highest performance (AUC 0.977), followed by TGF-β1 (AUC 0.973) and IGFBP1 (AUC 0.92). A lipidomic two-marker model achieved an AUC of 0.87. All diagnostic assessments were based on case–control studies; none conducted prospective validation. Conclusions: ME is a biologically relevant, non-invasive, and patient-acceptable biospecimen reflecting core endometriosis mechanisms and yielding promising diagnostic accuracy. The highest diagnostic performance was achieved for assays reflecting steroidogenic and growth-factor pathways (e.g., aromatase and TGF-β1). Standardization and prospective validation are needed before clinical adoption. Full article

Marrow-isolated adult multilineage inducible (MIAMI) cells are a subpopulation of mesenchymal stem/stromal cells (MSC) with enhanced self-renewal, multilineage plasticity, and anti-inflammatory properties, suggesting that their extracellular vesicles (MIA-EVs) may confer advantages over conventional MSC-EVs. MIAMI cells were transcriptionally profiled and expressed regenerative markers, including PDGFRB, CDX2, and TERT. We report the first successful isolation and characterization of MIA-EVs. EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis, transmission electron microscopy, flow cytometry, and surface markers. Cargo analysis identified growth factors (IGFBP-1, HGF, VEGF-D) and 19 highly expressed miRNA targeting survival, regenerative, and immune regulatory pathways. MIA-EVs were efficiently internalized, enhanced keratinocyte wound closure and suppressed osteosarcoma proliferation in vitro. Conditioned MIA-EVs reshaped pathway weighting without altering core regulatory identity, as a conserved 15-miRNA backbone persisted across naïve, irradiated, and cytokine-primed states. In contrast, a 9-miRNA core shared with MSC-EVs defined a basal mesenchymal framework, while MIA-EVs expanded regenerative, survival, and immune network connectivity. Similar to embryonic stem cell (ESC)-EVs, both MIA- and cytokine-primed EVs promoted M2 macrophage polarization, selectively upregulating IL1R2 and PPARG/STAT1, respectively. Meanwhile, MSC-EVs induced heterogeneous responses. These findings establish MIA-EVs as a conditioning-resistant, systems-regulated, cell-free platform with regenerative, immunomodulatory, and cytoprotective potential under hostile microenvironments. Full article

Purpose: To investigate the mechanisms by which plasma extracellular vesicles (EVs) from preterm infants with bronchopulmonary dysplasia (BPD) elicit inflammation and abnormal angiogenesis in neonatal mouse retinas. Methods: EVs from the plasma of 7-day-old preterm infants, born between 23^0/7 and 29^6/7 weeks of gestation, with BPD or without BPD (nBPD) at 36 weeks postmenstrual ages, were adoptively transferred into postnatal day 3 (P3) mice via intravenous retro-orbital sinus injection. Inflammation and pathological neovascularization in neonatal mouse retinas were examined by immunohistochemistry of retinal flat mounts for Allograft Inflammatory Factor 1 (AIF1), CD206, or Glial Fibrillary Acidic Protein (GFAP) and isolectin-B4 (IB4) staining on P17. Retinal inflammation-related transcripts were assessed by qRT-PCR. Proteomic profiles of BPD and nBPD EVs were examined by Liquid Chromatograph Mass Spectrometer/Mass Spectrometer (LC-MS/MS) and Gene Set Enrichment Analysis (GSEA). Results: Adoptively transferred EVs from BPD and nBPD infants crossed the blood–retinal barrier (BRB) in recipient mouse pups. BPD-EVs increased retinal activated microglia, Müller cells, and twisted proliferative neovascularization compared to nBPD-EVs. BPD-EVs also elevated retinal transcripts regulating inflammation and angiogenesis, including NOD-, LRR- and pyrin domain-containing protein 3 (Nlrp3), Apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc), Caspase 3 (Casp3), Caspase 8 (Casp8), Gasdermin D (Gsdmd), Il1β, Il6, Aif1, and Vascular endothelial growth factor (Vegf). Proteomics analysis revealed that BPD-EVs had significantly elevated levels of inflammation and angiogenesis-related proteins compared to nBPD-EVs. Conclusions: BPD-EVs promote inflammation and abnormal neovascularization by upregulating genes related to apoptosis and inflammation in neonatal mouse retinas. EV protein profiles suggest that elevated levels of proteins such as Defensin alpha 1B (DEFA1B), Insulin-like growth factor binding protein 2 (IGFBP2), CD5 antigen-like (CD5L), von Willebrand factor (vWF), and Tenascin C (TNC) in BPD-EVs may contribute to the observed inflammation and angiogenesis. Full article

Xin’anjiang water buffalo (XAJB) is crucial for meat production and agricultural activities in Anhui Province of China. To generate hypotheses regarding how DNA methylation might correlate with transcriptional differences in skeletal muscle, WGBS and RNA-seq were performed on three BF and three BM adult XAJB. The results revealed 31,333 differentially methylated cytosines (DMCs), 1961 differentially methylated regions (DMRs), and 230 differentially expressed genes (DEGs) in skeletal muscle between the two groups. The qRT-PCR results of ten DEGs (COL1A1, THBS1, SLITRK4, VIPR2, IGFBP6, WIF1, MMP16, LMOD3, NPR3 and MYLK4) enriched in protein digestion and absorption pathway, PPAR signaling pathway, ECM-receptor interaction pathway or PI3K-Akt signaling pathway were consistent with the RNA-seq results. Most methylation changes occurred in CG context, and sixteen genes were predicted as dual differential genes in both methylation and transcriptome. Moreover, CG methylation showed a significant negative correlation with gene expression within the 2 kb upstream region (rho = −0.42, p < 0.001). Given the limited number of animals examined, additional investigations with expanded cohorts are essential to verify the association between the methylome and transcriptome signatures underlying skeletal muscle in XAJB. Full article

Pancreatic cancer is a highly intractable malignancy that necessitates personalized treatment strategies. Conventional patient-derived models, such as three-dimensional organoids, are often limited by intellectual property constraints and high costs. In this study, we developed an affordable adherent culture system for patient-derived pancreatic cancer cells using a proprietary medium and laminin-coated dishes. Primary cultures were successfully established from 28 patients with pancreatic ductal adenocarcinoma, exceeding a 90% success rate. Validation of eight samples confirmed maintenance of epithelial cell adhesion molecule expression and preservation of oncogenic KRAS mutations. Transcriptomic profiling revealed consistent upregulation of a six-gene signature (FAP, IGFBP5, PRRX1, SPARC, WNT5A, and ADAMTS12), which is associated with malignancy. In vitro drug sensitivity assays revealed interpatient heterogeneity with preliminary clinical associations. In conclusion, this simplified platform provides high-purity cancer cells and serves as a functional precision medicine tool. Beyond conventional chemotherapy, this platform has the potential to support applications ranging from biomarker validation and exploratory preclinical testing of novel therapeutics, including immune checkpoint inhibitors and antibody–drug conjugates. This optimization can lead to personalized therapeutic strategies for pancreatic cancer. Full article

Growth rate is a key trait influencing productivity in aquaculture species, and its regulation often differs between males and females. In this study, Nanopore full-length RNA sequencing was used to investigate sex-specific growth regulation in the liver and brain of Pelteobagrus ussuriensis. Male and female groups each included three fast-growing and three slow-growing individuals. In liver tissue, 332 differentially expressed genes were identified in males and 266 in females. Male-biased genes were mainly involved in lipid and cholesterol metabolism, including the peroxisome proliferator-activated receptor signaling pathway, whereas females showed broader metabolic regulation involving carbohydrate, amino acid, and lipid metabolism, as well as growth-related genes such as IGFBP1, ESR1, and PGR. In brain tissue, fewer growth-associated differences were observed, with 26 differentially expressed genes in males and 45 in females. Alternative splicing analysis revealed strong tissue specificity, with approximately 2903 events in liver and 7412 in brain, dominated by exon skipping in liver and alternative first exon usage in brain. Isoform-level analysis further identified transcript differences not detected at the gene level, highlighting the importance of transcript diversity in growth regulation. Full article

The insulin-like growth factor (IGF) axis orchestrates hepatic development, regeneration, and metabolism, yet the roles of individual IGF-binding proteins (IGFBPs) remain incompletely defined. IGFBP-6, a high-affinity, IGF-II-preferring binding protein, has emerged as a context-dependent modulator of IGF bioavailability and cell signaling with additional IGF-independent actions. This review synthesizes current evidence on IGFBP-6 in liver biology and disease. We first outline hepatic expression, regulation, and post-translational processing of IGFBP-6 across development, homeostasis, and injury, and summarize its effects on canonical IGF-II/IGF1R signaling and downstream phosphatidylinositol 3-kinase—protein kinase B (PI3K–AKT) and rat sarcoma—mitogen-activated protein kinase (RAS–MAPK) pathways. We then evaluate experimental and clinical data linking IGFBP-6 to steatotic liver disease, inflammation, and fibrogenesis, including putative roles in hepatocyte stress responses, stellate cell activation, and extracellular matrix remodeling. Finally, we examine IGFBP-6 in primary liver cancers—hepatocellular carcinoma and cholangiocarcinoma—highlighting evidence for tumor-suppressive versus pro-migratory activities, potential crosstalk with hypoxia, Wnt/β-catenin and TGF-β signaling, and interactions with the tumor immune microenvironment. Across conditions, we assess the translational potential of IGFBP-6 as a circulating or tissue biomarker, its utility for patient stratification, and prospects for therapeutic targeting—either by modulating IGF-II sequestration or exploiting IGF-independent mechanisms. We conclude by identifying key knowledge gaps, methodological limitations, and priorities for future studies, including standardized measurement, cell-type-resolved profiling, and in vivo perturbation in clinically relevant models. Collectively, the review positions IGFBP-6 as a nuanced regulator of liver pathophysiology and a promising, yet underexplored, lever for diagnosis and therapy. Full article