{"publication_id":"79d2cfdb-60fe-4786-be4f-b55cacadc266","content_hash":"sha256:77146d606940263ceee328d9fa4d66feca00fb616ac848146bfbc3eee7a05610","nodes":[{"id":"79d2cfdb-60fe-4786-be4f-b55cacadc266","type":"publication","title":"Research Synthesis: Extracellular Matrix Stiffening — full paper"},{"id":"claim_1","type":"claim","text":"The evidence profile contains no sources classified primarily as direct clinical evidence, 50 adjacent clinical sources, and 7 mechanistic or model-system sources, with 1051 cross-study disagreements across the evidence base."},{"id":"claim_2","type":"claim","text":"No single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence, immune and inflammation, immune outcome classes, and negative signals cluster in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_3","type":"claim","text":"The conclusion is that extracellular matrix stiffening remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_4","type":"claim","text":"This manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-extracellular_matrix_stiffening-v06-DAILY-2026-06-06T00-02-32Z`."},{"id":"claim_5","type":"claim","text":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text."},{"id":"claim_6","type":"claim","text":"Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`."},{"id":"claim_7","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (contextual adjacent evidence, immune, immune and inflammation, longevity, safety and comorbidity, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_8","type":"claim","text":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified."},{"id":"claim_9","type":"claim","text":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim."},{"id":"claim_10","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_11","type":"claim","text":"| Contextual Adjacent Evidence | n=46; claims=816 | no extracted directional signal in 46/46 sources | 40 indirect; 4 mechanistic; 2 review | limited corpus depth in this outcome class |"},{"id":"claim_12","type":"claim","text":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate."},{"id":"claim_13","type":"claim","text":"46 included sources were assigned to this outcome class. Directional coding: null=46. Directness coding: indirect=40, mechanistic=4, review=2."},{"id":"claim_14","type":"claim","text":"5 included sources were assigned to this outcome class. Directional coding: null=5. Directness coding: indirect=5."},{"id":"claim_15","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=2, mechanistic=1."},{"id":"claim_16","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=2, mechanistic=1."},{"id":"claim_17","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_18","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: mechanistic=1."},{"id":"claim_19","type":"claim","text":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim."},{"id":"claim_20","type":"claim","text":"The curated corpus contains no randomized controlled trials and no prospective interventional studies with hard clinical endpoints such as mortality, cardiovascular events, or functional disability. All 59 included studies are either preclinical mechanistic investigations (e.g., Lee 2025, Moudt 2022) or observational cohorts (e.g., Alfano 2023, Ahmadi 2026), meaning the synthesis cannot establish causal directionality for extracellular matrix stiffening in human disease. The absence of randomized evidence precludes any estimate of treatment effect magnitude, and conclusions that depend on associational data must be interpreted with caution given the well-recognized limitations of surrogate endpoints (Ioannidis 2005)."},{"id":"claim_21","type":"claim","text":"Single-trial generalization risk is substantial across multiple outcome domains within this corpus. For example, skeletal fracture and bone outcomes are supported by only two observational cohorts — Schurman 2026 and Ahmadi 2026 — alongside one preclinical study (Pereira 2022), while immune mechanistic evidence rests almost entirely on a single in-vitro investigation (Lee 2025). When only one or two studies inform a domain, replication within the corpus is impossible, and apparent consistency may reflect shared methodological biases rather than biological robustness."},{"id":"claim_22","type":"claim","text":"Several clinically relevant endpoints were not measured in any study within the corpus. No study reported gait speed, handgrip strength, or other standard mobility and sarcopenia metrics (Cruz-Jentoft 2019), and no study assessed fall risk or patient-reported quality of life. The mechanistic evidence linking ECM stiffness to immune cell behavior (Lee 2025) and inflammation (Alfano 2023, Hu 2022) has not been translated into clinical outcomes such as infection incidence or inflammatory biomarker trajectories in intervention trials. Similarly, although ECM stiffening has been mechanistically linked to cancer progression (Xie 2025, Wang 2025c) and organ fibrosis (Junior 2023, Sun 2024), this corpus contains no longitudinal studies tracking whether biomechanical ECM changes precede clinical disease onset — leaving the directionality of these associations unresolved."},{"id":"claim_23","type":"claim","text":"For extracellular matrix stiffening, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging."},{"id":"claim_24","type":"claim","text":"This synthesis maps 59 included sources on Extracellular matrix stiffening across 6 outcome classes and 1051 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit."},{"id":"claim_25","type":"claim","text":"Across 59 curated reference papers, the evidence base for Extracellular matrix stiffening shows a context-dependent profile. Null findings dominate: contextual other, immune inflammation. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Extracellular matrix stiffening anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established."},{"id":"claim_26","type":"claim","text":"The strongest unresolved contrast is the agreement between Zhu 2023 and Zhang 2023b on contextual adjacent evidence (severity 1/5), which defines the boundary condition future studies must test rather than smooth over."},{"id":"claim_27","type":"claim","text":"This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary."},{"id":"claim_28","type":"claim","text":"| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |"},{"id":"claim_29","type":"claim","text":"| contextual adjacent evidence | 0 | 46 | null | direct interventional hard-endpoint gap |"},{"id":"claim_30","type":"claim","text":"| immune and inflammation | 0 | 5 | null | direct interventional hard-endpoint gap |"},{"id":"source_1","type":"source","study":"Harringtonine Attenuates Extracellular Matrix Degradation, Skin Barrier Dysfunction, and Inflammation in an In Vitro Skin Aging Model","year":2025,"doi":"10.3390/cimb47080642","url":"https://doi.org/10.3390/cimb47080642","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_2","type":"source","study":"Repeated application of passive mechanical stress produces selective metabolic and extracellular matrix adaptations in human skeletal muscle but does not prevent disuse-induced atrophy","year":2026,"doi":"10.1152/function.109.2025","url":"https://doi.org/10.1152/function.109.2025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_3","type":"source","study":"The Role of Extracellular Matrix and Inflammation in the Stratification of Bleeding and Thrombotic Risk of Atrial Fibrillation on Oral Anticoagulant Therapy: Insights from Strat-Af Study","year":2023,"doi":"10.3390/jcm12216866","url":"https://doi.org/10.3390/jcm12216866","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_4","type":"source","study":"In vitro and in vivo biocompatibility of a porcine cholecystic extracellular matrix (CECM) membrane for tissue regeneration","year":2025,"doi":"10.1038/s41405-025-00370-4","url":"https://doi.org/10.1038/s41405-025-00370-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_5","type":"source","study":"Progressive aortic stiffness in aging C57Bl/6 mice displays altered contractile behaviour and extracellular matrix changes","year":2022,"doi":"10.1038/s42003-022-03563-x","url":"https://doi.org/10.1038/s42003-022-03563-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_6","type":"source","study":"Effect of extracellular matrix stiffness on efficacy of Dapagliflozin for diabetic cardiomyopathy","year":2024,"doi":"10.1186/s12933-024-02369-x","url":"https://doi.org/10.1186/s12933-024-02369-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_7","type":"source","study":"Titin governs myocardial passive stiffness with major support from microtubules and actin and the extracellular matrix","year":2023,"doi":"10.1038/s44161-023-00348-1","url":"https://doi.org/10.1038/s44161-023-00348-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_8","type":"source","study":"The Presence of Adipose Tissue in Aortic Valves Influences Inflammation and Extracellular Matrix Composition in Chronic Aortic Regurgitation","year":2025,"doi":"10.3390/ijms26073128","url":"https://doi.org/10.3390/ijms26073128","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_9","type":"source","study":"Extracellular matrix protein 1 binds to connective tissue growth factor against liver fibrosis and ductular reaction","year":2024,"doi":"10.1097/HC9.0000000000000564","url":"https://doi.org/10.1097/HC9.0000000000000564","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_10","type":"source","study":"Effect of Extracellular Matrix Stiffness on Candesartan Efficacy in Anti-Fibrosis and Antioxidation","year":2023,"doi":"10.3390/antiox12030679","url":"https://doi.org/10.3390/antiox12030679","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_11","type":"source","study":"Adjusting the stiffness of a cell-free hydrogel system based on tissue-specific extracellular matrix to optimize adipose tissue regeneration","year":2023,"doi":"10.1093/burnst/tkad002","url":"https://doi.org/10.1093/burnst/tkad002","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_12","type":"source","study":"Extracellular matrix stiffness reduces DNA 6 ma level to facilitate colorectal cancer progression via disrupting P53 binding to CDKN1A promoter","year":2025,"doi":"10.1186/s40164-025-00704-w","url":"https://doi.org/10.1186/s40164-025-00704-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_13","type":"source","study":"A Vascular–Extracellular Matrix Molecular Program Identifies High-Risk Diffuse Glioma Across Independent Multi-Omics","year":2026,"doi":"10.3390/cancers18101652","url":"https://doi.org/10.3390/cancers18101652","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_14","type":"source","study":"Extracellular Matrix Stiffness-Induced Mechanotransduction of Capillarized Liver Sinusoidal Endothelial Cells","year":2024,"doi":"10.3390/ph17050644","url":"https://doi.org/10.3390/ph17050644","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_15","type":"source","study":"Extracellular Matrix Stiffness and TGFβ2 Regulate YAP/TAZ Activity in Human Trabecular Meshwork Cells","year":2022,"doi":"10.3389/fcell.2022.844342","url":"https://doi.org/10.3389/fcell.2022.844342","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_16","type":"source","study":"Altered extracellular matrix structure and elevated stiffness in a brain organoid model for disease","year":2025,"doi":"10.1038/s41467-025-59252-w","url":"https://doi.org/10.1038/s41467-025-59252-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_17","type":"source","study":"Efficacy of decellularized extracellular matrix (dECM) for articular cartilage repair in osteoarthritis (OA): a systematic review and meta-analysis","year":2025,"doi":"10.1186/s13018-025-05881-2","url":"https://doi.org/10.1186/s13018-025-05881-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_18","type":"source","study":"Extracellular matrix stiffness aggravates urethral stricture through Igfbp3/Smad pathway","year":2023,"doi":"10.1038/s41598-023-41584-6","url":"https://doi.org/10.1038/s41598-023-41584-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_19","type":"source","study":"Effects of aging on the biomechanical properties of the lung extracellular matrix: dependence on tissular stretch","year":2024,"doi":"10.3389/fcell.2024.1381470","url":"https://doi.org/10.3389/fcell.2024.1381470","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_20","type":"source","study":"Tissue and extracellular matrix remodeling of the subchondral bone during osteoarthritis of knee joints as revealed by spatial mass spectrometry imaging","year":2026,"doi":"10.1038/s41413-025-00495-0","url":"https://doi.org/10.1038/s41413-025-00495-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_21","type":"source","study":"Defined extracellular matrix compositions support stiffness-insensitive cell spreading and adhesion signaling","year":2023,"doi":"10.1073/pnas.2304288120","url":"https://doi.org/10.1073/pnas.2304288120","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_22","type":"source","study":"Extracellular Matrix Tissue Patch for Pulmonary Artery Repair in Pediatric Cardiac Surgery: A Single-Center Experience","year":2026,"doi":"10.3390/jcm15031177","url":"https://doi.org/10.3390/jcm15031177","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_23","type":"source","study":"Extracellular Matrix–MYCAF Signatures Correlate with Resistance to Neoadjuvant aPD-L1 Immune Checkpoint Inhibition with Durvalumab + Metformin in HPV+ HNSCC","year":2025,"doi":"10.1158/1078-0432.CCR-25-1098","url":"https://doi.org/10.1158/1078-0432.CCR-25-1098","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_24","type":"source","study":"3D Printing of Extracellular Matrix‐Based Multicomponent, All‐Natural, Highly Elastic, and Functional Materials toward Vascular Tissue Engineering","year":2023,"doi":"10.1002/adhm.202203044","url":"https://doi.org/10.1002/adhm.202203044","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_25","type":"source","study":"Preservation of the naïve features of mesenchymal stromal cells in vitro: Comparison of cell- and bone-derived decellularized extracellular matrix","year":2022,"doi":"10.1177/20417314221074453","url":"https://doi.org/10.1177/20417314221074453","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_26","type":"source","study":"Effect of miRNA-218-5p on Proliferation, Migration, Apoptosis and Inflammation of Vascular Smooth Muscle Cells in Abdominal Aortic Aneurysm and Extracellular Matrix Protein","year":2022,"doi":"10.18502/ijph.v51i11.11166","url":"https://doi.org/10.18502/ijph.v51i11.11166","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_27","type":"source","study":"In need of age‐appropriate cardiac models: Impact of cell age on extracellular matrix therapy outcomes","year":2023,"doi":"10.1111/acel.13966","url":"https://doi.org/10.1111/acel.13966","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_28","type":"source","study":"Lysyl-Oxidase Dependent Extracellular Matrix Stiffness in Hodgkin Lymphomas: Mechanical and Topographical Evidence","year":2022,"doi":"10.3390/cancers14010259","url":"https://doi.org/10.3390/cancers14010259","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_29","type":"source","study":"Tissue response and clinical outcomes after cardiovascular use of porcine small intestinal small intestinal submucosal extracellular matrix: a systematic review","year":2025,"doi":"10.3389/fcvm.2025.1532157","url":"https://doi.org/10.3389/fcvm.2025.1532157","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_30","type":"source","study":"Association of Epicardial Adipose Tissue Adipocytes Hypertrophy with Biomarkers of Low-Grade Inflammation and Extracellular Matrix Remodeling in Patients with Coronary Artery Disease","year":2023,"doi":"10.3390/biomedicines11020241","url":"https://doi.org/10.3390/biomedicines11020241","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_31","type":"source","study":"Survivin regulates intracellular stiffness and extracellular matrix production in vascular smooth muscle cells","year":2023,"doi":"10.1063/5.0157549","url":"https://doi.org/10.1063/5.0157549","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_32","type":"source","study":"Key role for Rac in the early transcriptional response to extracellular matrix stiffness and stiffness-dependent repression of ATF3","year":2023,"doi":"10.1242/jcs.260636","url":"https://doi.org/10.1242/jcs.260636","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_33","type":"source","study":"Suppression of METTL3 expression attenuated matrix stiffness-induced vaginal fibroblast-to-myofibroblast differentiation and abnormal modulation of the extracellular matrix in pelvic organ prolapse","year":2025,"doi":"10.1097/CM9.0000000000003409","url":"https://doi.org/10.1097/CM9.0000000000003409","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_34","type":"source","study":"Extracellular Matrix Tissue Patch for Aortic Arch Repair in Pediatric Cardiac Surgery: A Single-Center Experience","year":2025,"doi":"10.3390/jcm14113955","url":"https://doi.org/10.3390/jcm14113955","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_35","type":"source","study":"Extracellular matrix stiffness regulates colorectal cancer progression via HSF4","year":2025,"doi":"10.1186/s13046-025-03297-8","url":"https://doi.org/10.1186/s13046-025-03297-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_36","type":"source","study":"Sox9 Accelerates Vascular Aging by Regulating Extracellular Matrix Composition and Stiffness","year":2024,"doi":"10.1161/CIRCRESAHA.123.323365","url":"https://doi.org/10.1161/CIRCRESAHA.123.323365","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_37","type":"source","study":"CD248 ‐expressing cancer‐associated fibroblasts induce non‐small cell lung cancer metastasis via Hippo pathway‐mediated extracellular matrix stiffness","year":2024,"doi":"10.1111/jcmm.70025","url":"https://doi.org/10.1111/jcmm.70025","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_38","type":"source","study":"Ecliptasaponin A attenuates renal 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