Search Results (2,908)

Background and Objectives: Superficial peritoneal endometriosis (SPE) remains one of the most difficult endometriosis phenotypes to diagnose non-invasively, because lesions are frequently small, multifocal, and poorly detectable using conventional imaging. Diagnostic laparoscopy therefore remains the reference standard for direct visualization of superficial peritoneal lesions. However, the inconsistent relationship between visible lesion burden and pain severity, together with the multifactorial nature of chronic pelvic pain, highlights the limitations of a purely lesion-based diagnostic model. This narrative review reassesses SPE from a cautious functional and molecular perspective, focusing on clinically established evidence, emerging but incompletely validated tools, and hypothesis-generating concepts. The novelty of this review lies in its specific focus on SPE as an unresolved diagnostic phenotype and in the proposed integration of surgical diagnosis, expert imaging, pain phenotyping, empirical treatment response, and molecular research within a non-replacement framework. Materials and Methods: A narrative literature review was performed using PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library for English-language articles published between January 2010 and April 2026. The search focused on SPE, diagnostic laparoscopy, dynamic transvaginal ultrasound, sliding sign, chronic pelvic pain, hormonal treatment response, neuroinflammation, liquid biopsy, circulating biomarkers, epigenetics, and microbiome research. Results: Dynamic transvaginal ultrasound, sliding sign assessment, pelvic organ mobility evaluation, and tenderness-guided examination may provide indirect functional information in selected patients with suspected SPE, but they remain operator-dependent and insufficiently standardized for this phenotype. Response to hormonal therapy may support clinical reasoning, but it has low specificity and may also reflect improvement of adenomyosis, primary dysmenorrhea, ovulation-related pain, abnormal uterine bleeding, or other estrogen-sensitive conditions. Liquid biopsy and molecular biomarkers, including circulating microRNAs, extracellular vesicles, cell-free DNA, inflammatory mediators, epigenetic signatures, adipokine-related markers, and microbiome-related signals, remain investigational and require phenotype-specific validation. Conclusions: Functional and molecular stratification of suspected SPE represents a promising research direction rather than a current clinical standard. Laparoscopy remains essential when definitive diagnosis or surgical treatment is required, particularly in patients with infertility, refractory symptoms, suspicious imaging, or suspected complex disease. Future validated models may help integrate clinical phenotype, expert imaging, treatment response, pain mechanisms, and molecular profiles to support more individualized and selective diagnostic pathways. Full article

Escherichia coli is a genetically diverse species encompassing both commensal and pathogenic lineages capable of transitioning among various hosts. Within a One Health framework, we conducted a targeted screening of 38 E. coli strains isolated from wildlife, livestock, and food reservoirs to characterize their pathogenic potential by integrating genomic and phenotypic approaches. In vitro functional assays, including biofilm formation, surface motility, and adherence and invasion of HEK-293 epithelial cells, were statistically evaluated using the non-parametric Mann–Whitney U test. Phenotypic analyses revealed that extraintestinal pathogenic (ExPEC) and uropathogenic E. coli (UPEC) strains, particularly those belonging to the high-risk ST117 clone, exhibited significantly enhanced adherence and internalization capacities. These virulent phenotypes strongly correlated with specific genetic signatures involved in iron acquisition and epithelial invasion (chuA, fyuA, vat, and tia), underscoring that the convergence of ExPEC/UPEC determinants drives increased colonization potential. Genomic characterization further revealed that despite high virulence and widespread antimicrobial resistance, the CRISPR/Cas subtype I-E system was highly prevalent (93.8%), displaying structural variations frequently driven by insertion sequences. Spacer analyses identified limited homology to plasmids and phages, suggesting past mobilome interactions rather than active restriction of current horizontal gene transfer. Overall, these findings illustrate how phenotypic traits of high-risk clones match their genomic virulence platforms. The convergence of multidrug resistance and pathogenic fitness across human, animal, and environmental interfaces underscores the need for integrated molecular surveillance in a One Health context. Full article

Gliomas are the most common group of primary brain tumors, among which glioblastoma multiforme (GBM) is characterized by a particularly poor prognosis and the limited effectiveness of available treatments. Ophiobolin A (OP-A), a natural sesterterpenoid, exhibits promising anticancer properties, including the ability to cross the blood-brain barrier and induce paraptosis-like cell death. However, the molecular mechanisms underlying its action, especially in the early phase of the cellular response, remain not fully understood. The aim of this study was to analyze early changes in the expression of genes associated with apoptosis, ferroptosis, and antioxidant mechanisms in T98G and U118MG glioma cells exposed to OP-A. Gene expression was assessed by RT-qPCR, apoptosis was evaluated using Annexin V/PI staining and flow cytometry, and treatment-induced morphological changes were documented by brightfield microscopy. Statistical analysis was performed using the Mann–Whitney U test. Descriptive Annexin V/PI analysis showed a lower proportion of viable cells and a higher proportion of early apoptotic cells in the analyzed OP-A-treated T98G and U118MG samples compared with the corresponding vehicle-control samples. These preliminary observations were based on technical replicates from a single biological experiment and require confirmation in independent biological replicates. Transcriptional profiling revealed a shift toward a pro-apoptotic phenotype, characterized by increased BAX and FAS expression together with a trend toward reduced BCL2 expression, whereas ferroptosis-associated genes remained largely unchanged. Notably, SLC7A11 upregulation suggested activation of compensatory antioxidant mechanisms in response to OP-A treatment. In T98G cells, OP-A induced a distinct and reproducible transcriptional signature that enabled accurate discrimination from control conditions (AUC = 0.833). Feature importance and SHAP analyses identified BAX as the most informative predictor, followed by SLC7A11 and FAS, with bootstrap validation confirming BAX as a stable marker. Pathway analysis demonstrated selective activation of apoptosis- and cysteine metabolism-related pathways, while hierarchical clustering revealed that OP-A generated a transcriptional profile distinct from oxidative stress-inducing agents. The predictive performance of this molecular signature was cell-line dependent, showing weaker discrimination in U118MG cells.Short-term OP-A exposure in T98G and U118MG cells was associated with exploratory trends in apoptosis- and redox-related gene expression and a higher proportion of Annexin V-positive cells. The machine-learning analyses identified candidate discriminatory features within this limited dataset but should be regarded as hypothesis-generating. Larger studies with independent biological replication, additional GBM models, different exposure conditions, and functional validation are required to confirm these observations and clarify the mechanism of OP-A action. Full article

Background: Metastasis is the leading cause of mortality in lung cancer and is regulated by multiple molecular mechanisms, including microRNAs (miRNAs). Although cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT) contribute to metastatic progression, the miRNA networks underlying these phenotypes remain poorly characterized in non-small cell lung cancer (NSCLC). Aim: To identify miRNA signatures associated with CSCs and EMT in NSCLC and functionally characterize hsa-let-7a-3p. Methods: EMT was induced in A549 and NCI-H1975 cells by dCas9-mediated activation of TWIST, whereas CSC-enriched populations were generated by CD133-based sorting and stem cell culture conditions. Small RNA sequencing, bioinformatic analyses, qPCR validation, and functional assays were performed to identify and characterize phenotype-associated miRNAs. Results: Small RNA sequencing identified distinct miRNA expression profiles associated with EMT and CSC enrichment. Comparative analysis identified 13 commonly downregulated and 13 commonly upregulated miRNAs shared by CSCs from A549 and H1975 cells, suggesting conserved post-transcriptional regulatory mechanisms. Functional enrichment and miRNA–target interaction network analyses linked the miRNA signatures to pathways involved in epithelial plasticity, stemness, and tumor progression, including Wnt, TGF-β, mTOR, focal adhesion, adherens junction, and regulation of the actin cytoskeleton. Among the dysregulated miRNAs, hsa-let-7a-3p was consistently upregulated in CD133⁺ CSC-enriched cells from both NSCLC cell lines. Functional assays showed that hsa-let-7a-3p overexpression significantly reduced clonogenic capacity and showed a trend toward decreased invasion without affecting proliferation. Conclusion: This study identifies miRNA signatures associated with CSC-enriched and EMT-associated phenotypes in NSCLC and demonstrates that these signatures represent coordinated post-transcriptional regulatory programs involved in epithelial plasticity, stemness, and metastatic progression. Functional validation of hsa-let-7a-3p further supports its role as a context-dependent regulator of CSC biology and highlights the potential of miRNA signatures as diagnostic biomarkers in NSCLC. Full article

The human placenta is a temporary organ structured to optimize exchange between the maternal and fetal circulatory systems. Its fetal component consists of highly branched chorionic villi, which are anchored to the maternal uterine wall and project into the intervillous space. The outer surface of these villi is lined by a multinucleated, continuous layer called the syncytiotrophoblast, which is supported by an underlying layer of proliferative cytotrophoblast cells and the invasive extravillous trophoblast (EVT). This cellular bilayer forms a selective barrier that directly bathes in maternal blood, allowing for the efficient transfer of oxygen and nutrients while structurally preventing the direct mixing of maternal and fetal blood cells. Human placental studies have been stymied by ethical and accessibility constraints. Stem cell biology has now revolutionized the capacity to model human placental development, in particular with the derivation of human trophoblast stem cells (hTSCs) and organoids. Authentic, self-renewing human trophoblast stem cells (hTSCs) were first derived not from pluripotent stem cells but from primary tissue—first-trimester villous cytotrophoblasts and blastocysts. Derivation from human pluripotent stem cells (PSCs) followed only subsequently, along two principal routes: conversion of naive PSCs, which retain extraembryonic competence, and induction from primed PSCs, as well as by direct reprogramming of somatic cells to induced hTSCs. An important advance underlying these improvements is the mapping of a global reprogramming roadmap. Multi-omic and lineage-tracing experiments have mapped the stepwise transcriptional and epigenetic conversions of fibroblasts to hTSCs, including sequential chromatin reconfiguration, trophoblast gene network activation, and repression of somatic signatures. These results identify major regulatory bottlenecks and intermediate states, improving reprogramming fidelity. The derivation of stem-cell-based trophoblast organoids now enables complex modeling of placental architecture, function, and disease susceptibility in vitro. These organoids accurately recapitulate placental barrier functions and immunological features, allowing for examinations of maternal–fetal health, pregnancy disorders, and placental infection response to viruses like cytomegalovirus and SARS-CoV-2. Looking ahead, the integration of reprogramming and organoid technologies will propel patient-specific and tailor-made models for personalized diagnostics, drug screening, and mechanism studies. As we unravel the molecular ballet of trophoblast induction, such discoveries have the potential to bridge basic translational gaps in reproductive biology and maternal–fetal medicine. Full article

Choroidal neovascularization (CNV) is a common and serious complication in various retinal diseases that involves the growth of new blood vessels from the choroid into the subretinal space, leading to a visual threat. Its underlying mechanism has not been fully uncovered. Discovering new genes related to CNV is an important way to reveal its molecular mechanisms. In this study, we used DisGeNET as the initial data source to identify genes related to CNV. The gene cluster method and additional screening tests were designed to explore the genetic landscape related to CNV. Our comprehensive analysis revealed many genes with high confidence, specifically identifying novel candidates that traditional topological methods missed. Notably, we identified SERPINE1, COL1A1, and ANGPT1 as unique gene signatures using our network embedding approach. Functionally, SERPINE1 regulates the plasminogen activation system to control proteolytic balance, COL1A1 maintains the structural integrity of the extracellular matrix during invasion, and ANGPT1 is critical for the maturation and stabilization of nascent vessels. Meanwhile, some genes were also identified by other methods, such as MMP2, a regulator of extracellular matrix degradation. The newly found genes are essential for understanding the process that initiates CNV. Full article

Background/Objectives: Brain arteriovenous malformations (bAVMs) are complex cerebrovascular lesions that carry a substantial risk of intracranial hemorrhage, yet the biological mechanisms underlying vascular remodeling remain incompletely understood. As increasing evidence suggests that inflammatory processes contribute to vascular remodeling and bAVM progression, this study aimed to characterize the cellular composition of the immune microenvironment in human bAVMs at single-cell resolution and to identify immune cell populations associated with transcriptional programs related to angiogenesis and extracellular matrix remodeling. Methods: Publicly accessible single-cell RNA sequencing data from five human bAVM samples and five control brain specimens were analyzed. After quality control and data integration, immune cell types were annotated based on canonical marker gene expression. To assess biological processes relevant to vascular remodeling, the expression of predefined gene sets associated with angiogenesis and extracellular matrix remodeling, derived from the Molecular Signatures Database (MSigDB), was quantified across cell populations using rank-based gene set scoring (UCell). Differences between bAVM and control samples were evaluated at the sample level using the Wilcoxon rank-sum test. For each immune cell type, mean UCell scores were calculated per biological sample and compared between groups. To account for multiple comparisons across cell types, p-values were adjusted using the Benjamini–Hochberg procedure. Results: After quality control, 46,360 immune cells were analyzed. Compared with control tissue, bAVMs showed numerically higher proportions of lymphoid (activated T cells and CD8 T cells) and myeloid populations (M1-like macrophages, monocytes, and dendritic cells). Angiogenesis-related transcriptional activity was highest in myeloid cells and significantly increased in bAVMs, particularly in M1-like macrophages (UCell score 0.22 vs. 0.13), dendritic cells (0.16 vs. 0.10) and monocytes (0.20 vs. 0.15), whereas proliferating CD8 T cells showed a lower score (0.04 vs. 0.05; adjusted p = 0.040 for all four). Extracellular matrix-related programs showed a similar but weaker and non-significant pattern in myeloid populations (e.g., monocytes, dendritic cells, microglia-like cells; adjusted p = 0.09). Conclusions: Our findings identify myeloid cells, particularly M1-like macrophages, monocytes and dendritic cells, as important immune populations associated with angiogenesis in bAVMs. These findings highlight a potential role of immune-driven vascular remodeling in the pathophysiology of bAVMs. Full article

Integrated proteomics and untargeted metabolomics were employed to systematically characterize molecular differences between Acipenser schrenckii embryos with normal versus abnormal 24 h post-fertilization (24 hpf), which were classified as high-quality (HQ) and poor-quality (PQ) groups. Among 1636 proteins and 1102 metabolites, 220 differentially expressed proteins (DEPs) and 365 differential metabolites (DMs) were identified. Functional enrichment demonstrated that HQ samples were predominantly enriched in pathways associated with amino acid biosynthesis, glycolysis/tricarboxylic acid cycle, nucleotide metabolism, and mRNA surveillance, which collectively supported material accumulation, energy supply, and embryonic developmental competence. In contrast, PQ samples were mainly enriched in oxidative phosphorylation, mitochondrial stress response, arachidonic acid metabolism, and immune and inflammatory signaling pathways, indicating severe lipid metabolic disorders and excessive oxidative stress. Spearman correlation analysis identified L-pyroglutamic acid and ascorbic acid as core correlated metabolic hubs associated with high-quality eggs, while natamycin and tetrahydrocorticosterone were correlated characteristic metabolic signatures enriched in deteriorated eggs. Key protein nodes showing strong correlations with 24 hpf developmental phenotypes included GAPDH, glutathione S-transferase, and CYP450 2E1. Collectively, this study reveals divergent correlated molecular profiles linked to normal versus abnormal 24 hpf development and screens correlative multi-omics candidate signatures for distinguishing well-developed and deteriorated oocytes. Full article

CRISPR (clustered regularly interspaced short palindromic repeats)-based genome engineering is reshaping how environmental contamination can be interrogated and remediated, offering a level of programmability and specificity that conventional physicochemical workflows seldom match. Microplastics polymer fragments below 5 mm that now pervade virtually every ecosystem are especially difficult to monitor and remove because of their chemical heterogeneity, sub-millimeter size, and capacity to adsorb co-pollutants. This review examines how the molecular logic of CRISPR-Cas systems is being repurposed for two complementary goals: sensitive analytical detection and microbially driven degradation of plastic particles. We first outline the biochemistry of Cas-mediated cis- and trans-cleavage that underpins isothermal, amplification-free biosensing, and then survey direct strategies, in which polymer-binding DNA (deoxyribonucleic acid) aptamers are coupled to Cas12a (CRISPR-associated protein 12a), alongside indirect strategies that read out the molecular stress signatures provoked by microplastic exposure in sentinel organisms and plastisphere communities. On the remediation side, we discuss how targeted editing, CRISPR interference, and rationally assembled microbial consortia enhance enzymatic depolymerization and redirect carbon flux toward valuable bioproducts. By integrating detection and remediation within a single conceptual framework, we identify the principal bottlenecks, aptamer selectivity in complex matrices, reagent stability under field conditions, and host metabolic burden, and outline research priorities for translating these tools from proof of concept toward deployable environmental technologies. Full article

Background: Prostate cancer (PCa) exhibits strong multidimensional heterogeneity. The dynamic evolution of Luminal subsets and their crosstalk with the tumor microenvironment (TME) during malignant progression remain poorly understood. Conventional single-cell transcriptomics lacks spatial context, while low-resolution spatial technologies cannot resolve single-cell and subcellular interactions. This study aimed to map a high-resolution spatial transcriptomic atlas to characterize Luminal subset heterogeneity and stromal crosstalk across progressive PCa lesions. Methods: We used high-resolution CosMx spatial molecular imaging (SMI) to profile 6 treatment-naive PCa patients and constructed a single-cell spatial transcriptomic atlas covering 385 fields of view and 154,168 high-quality cells. Unsupervised clustering, functional enrichment, cell–cell communication analysis, and flow cytometry were performed. Results: We identified 28 cell clusters, including 8 Luminal subsets (0–7) and 9 Fibroblast subsets (0–8). Pathological microregion-specific spatial distribution was observed: Luminal 0–2 dominated in BPH/PIN, while Luminal 3–7 were enriched in poorly differentiated PCa and vacuolated adenocarcinoma. These subsets were functionally linked to androgen resistance, EMT, and immune regulation. COLLAGEN, FN1, and LAMININ were identified as key pathways mediating pathological-specific tumor–stromal crosstalk. Flow cytometry verified T-cell exhaustion and immunosuppression in the TME. Conclusions: This study delineated pathological microregion-specific Luminal subset plasticity and dynamic epithelial–stromal communication across the full spectrum of PCa lesions. The uncovered molecular signatures offered mechanistic clues linking EMT, hormone resistance, and local immune status during lesion evolution. Our spatial atlas provided preliminary molecular evidence to support pathological stratification and targeted precision therapeutic strategies for PCa. Full article

Extracellular Vesicles (EVs) have been increasingly recognized as mediators of intercellular communication in pancreatic tissues, carrying molecular cargo reflective of their cellular origin; however, their direct isolation from solid tissue remains technically challenging due to the high enzymatic activity, lipid content, and structural fragility of the pancreas. Here, we establish a pancreas-adapted and reproducible workflow for the isolation of EVs directly from human and mouse pancreatic tissues across tumor and non-tumorous contexts. This approach integrates controlled tissue processing, gentle enzymatic-mechanical dissociation, and sequential centrifugation to enable efficient vesicle recovery while preserving structural integrity and minimizing contamination. The isolated EVs exhibited characteristic size distributions, intact morphology, and enrichment of canonical EV markers, accompanied by depletion of intracellular components. Quantitative analyses demonstrated high reproducibility across independent isolations, with a coefficient of variation of less than 6%. Proteomic profiling revealed selective enrichment of vesicle-associated proteins and preservation of molecular differences between tumor and normal pancreatic tissues, indicating that tissue-derived EVs retain disease-associated protein signatures. Together, these results establish a standardized framework for pancreas-derived EV isolation that supports reproducible downstream analyses and facilitates molecular characterization of pancreatic tissues. Full article

Neurodegenerative diseases represent a major and growing global health burden characterized by progressive neuronal dysfunction, axonal degeneration, and irreversible neural tissue loss. Increasing evidence identifies oxidative stress as one of several interacting pathogenic mechanisms in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and several optic neuropathies. Interest has increasingly focused on the brain-retina axis, as the retina and optic nerve share structural, metabolic, and molecular features with the central nervous system and may provide accessible insights into neurodegeneration. This scoping review mapped current evidence on oxidative stress in neurodegeneration, emphasizing cranial nerve involvement, optic nerve vulnerability, retinal ganglion cell degeneration, visual dysfunction, oxidative biomarkers, and emerging therapeutic strategies. The review followed established methodological frameworks and PRISMA-ScR recommendations; no formal risk-of-bias appraisal was undertaken, consistent with scoping-review methodology. The literature shows that oxidative stress interacts with mitochondrial dysfunction, neuroinflammation, impaired mitophagy, ferroptosis, and altered bioenergetics, contributing to neuronal injury in cerebral and retinal disorders. Retinal ganglion cells appear particularly vulnerable because of their high metabolic demands and reliance on oxidative phosphorylation. Glaucoma and other optic neuropathies share molecular signatures with central neurodegenerative diseases. Retinal imaging and oxidative biomarkers show promise for diagnosis, monitoring, and stratification. The evidence base is nonetheless dominated by preclinical work; biomarker performance is inconsistent across matrices and assay platforms and most antioxidant clinical trials have been negative. Oxidative stress is therefore best regarded as one interacting node of a broader pathogenic network rather than a universal or predominant driver and the brain-retina continuum as a mechanistically plausible but not yet clinically validated framework for biomarker-guided neuroprotection. Full article

Background: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous chronic airway disorders characterized by complex interactions among inflammation, immune dysregulation, environmental exposures, and tissue remodeling. Conventional clinical classifications based on symptoms, lung function, and exacerbation history often fail to fully capture the biological mechanisms underlying disease progression and therapeutic variability. Methods: This narrative review summarizes current evidence regarding the biological and clinical significance of YKL-40, mannose-binding lectin (MBL), and epigenetic remodeling in asthma and COPD, with particular emphasis on the inflammation–epigenetic axis and its potential role in disease phenotyping and precision medicine. Results: Available evidence suggests that YKL-40, MBL, and epigenetic signatures represent complementary biomarker layers reflecting tissue remodeling, innate immune variability, and cumulative inflammatory adaptation, respectively. Chronic inflammatory signaling, oxidative stress, and epigenetic remodeling may contribute to persistent molecular memory and phenotypic stabilization, providing a mechanistic framework for understanding disease heterogeneity and progression. Advances in multi-omics technologies, artificial intelligence, and machine learning are further supporting the development of integrated multimarker models. Conclusions: YKL-40, MBL, and epigenetic signatures should currently be considered complementary research variables rather than validated clinical tools. Their translation requires disease-specific assay standardization, prospective evaluation against prespecified outcomes, external validation, and evidence that biomarker-guided decisions improve patient care. Full article

IgA nephropathy (IgAN) is a primary glomerular disease with various clinical features, disease progression, and therapeutic responses that affects people worldwide. Currently, risk stratification depends primarily on clinical variables, together with the Oxford MEST-C classification, which indicates structural damage. However, these approaches only provide a limited explanation of the molecular mechanisms responsible for the disease. Recent proteomic discoveries have enabled researchers to characterize proteins not only in blood plasma and urine but also in kidney tissues, opening new avenues for understanding the underlying biology of IgAN. Our review addresses existing findings in plasma proteomic studies and, at the same time, brings into the picture developments in urinary and tissue proteomic profiling, thereby demonstrating that molecular profiling has been essential for further understanding of IgAN pathogenesis. Several research studies highlight complement system dysregulation, immune system overactivity, extracellular matrix remodeling, and metabolic disturbances as the leading factors linked to disease activity and progression. Even after many years in biomarker discovery, the development and clinical application of single plasma-based molecules as markers for disease detection remain challenging. Proteomic signatures based on the various processes involved in a single disease consistently outperform single protein identification in describing complexity and distinguishing molecular endotypes. We also present the current status of proteomic-based profiling methods, cross-linking proteomics with other data sources, and the remaining clinical application barriers. Through the development of this technology, proteomics has not only enabled the discovery of new biomarkers but also provided a framework for viewing IgAN as a heterogeneous disease comprising distinct molecular endotypes. Overall, current evidence indicates that proteomics is evolving from biomarker discovery toward molecular disease classification, with the potential to improve prognostication, guide mechanism-based therapeutic selection, and advance precision nephrology in IgAN. Full article

Autophagy–lysosome dysfunction accompanies dermal fibroblast ageing, yet whether remodelling is transcriptional or post-transcriptional in primary human cells remains unresolved. We reanalysed the Genetic and Epigenetic Signatures of Translational Ageing Laboratory Testing(GESTALT) paired RNA sequencing (RNA-seq) and tandem mass tag (TMT) proteome from 82 donors (aged 22–89) using Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) for supervised multi-omics integration, weighted gene co-expression network analysis (WGCNA), external Genotype-Tissue Expression(GTEx) transcriptomic comparison, network medicine proximity mapping and CDOCKER molecular docking. Three analyses converged on the autophagy–lysosome axis: Kyoto Encyclopaedia of Genes and Genomes (KEGG) Lysosome ranked first in discordant-quadrant analysis; gene set enrichment analysis (GSEA) identified vacuole organisation and macroautophagy as the top age-upregulated Gene Ontology (GO) terms; and WGCNA recovered KEGG Lysosome in the brown module. Module regression localised most proteomic age signals to the lysosomal degradative-capacity module, whereas the proteasome was unaffected. McNemar testing and GTEx comparison supported a protein-side, post-transcriptional origin. TCIRG1, CTSA and ATP6V0D1 were recurrent hubs. Network proximity computationally prioritised hydroxytyrosol as a lysosomal-degradative-capacity-preferential candidate, and CDOCKER on cathepsin A linked its advantage over tyrosol to an ortho-hydroxyl group forming additional hydrogen bonds. These results support protein-layer-dominant autophagy–lysosome remodelling as a feature of dermal fibroblast ageing and suggest a cell-type-resolved computational route from ageing proteomics to testable dietary candidates. Full article