TGF-β1 promotes collagen synthesis in systemic sclerosis via upregulating P4HA3.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:41127814", "kind": "science-record", "revision": 4, "content_hash": "sha256:3ac0b289bb1c7f7d6633ae8a887bc7d9c9eeacf1f72fbb77e2ee463f5f67ab1a", "created_at": "2026-11-01T20:31:10Z", "updated_at": "2026-11-01T22:57:20Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "TGF-β1 promotes collagen synthesis in systemic sclerosis via upregulating P4HA3.", "doi": "10.1016/j.jtauto.2025.100323", "pmid": "41127814", "authors": ["Zhaopeng Chen", "Yinru Lin", "Yayi Huang", "Zhixian Chen", "Yao Gong", "Zhiduo Hou", "Ling Lin"], "journal": "Journal of translational autoimmunity", "year": 2025, "abstract": "Objective: Systemic sclerosis (SSc) is a complex autoimmune disease resulting in fibrosis of skin and internal organs. Despite progress in treatment, SSc carries high mortality due to organ fibrosis. This study aimed to identify a potential antifibrotic therapeutic for the treatment of SSc.\nMethods: SSc bioinformatics data (GSE181549 and GSE138669) were obtained from the public Gene Expression Omnibus (GEO) database. Subsequently, we conducted differential analysis, Protein-protein interaction (PPI) network construction, gene enrichment analysis to identify a key fibrotic gene, followed by verification.\nResults: A total of 107 differentially expressed genes were identified through analysis between SSc patients and healthy controls. P4HA3 (α subunit of Collagen prolyl 4-hydroxylases, C-P4Hs) was identified by PPI network analysis. P4HA3 was the sole upregulated gene and positively correlated with the modified Rodnan skin score. PI3K/AKT signaling pathway was enriched by GSEA for single-gene to obtain P4HA3-related pathways. Single-cell analysis detected predominant TGF-β1 upregulation in immune cells, particularly in CD14 + CD16 - monocytes, and P4HA3 showed elevated expression in SFRP2 high fibroblasts. Immunohistochemistry indicated that P4HA3- and TGF-β1-positive cell numbers were elevated in the dermal layers of SSc patients. P4HA3 was also elevated in bleomycin-treated mice and TGF-β1-induced human fibroblasts. Inhibition of C-P4Hs ameliorated experimental fibrosis in bleomycin-treated mice and TGF-β1-induced human fibroblasts. Hydroxyproline levels were reduced following P4HA3 knockdown in human fibroblasts.\nConclusion: Our results suggest that P4HA3 is upregulated by TGF-β1 secreted from immune cells to promote collagen synthesis in SSc. Inhibition of C-P4Hs is a potential therapeutic approach for SSc fibrosis.", "claims": [{"id": "claim-method", "statement": "The raw counts of gene expression data in GSE181549 were normalized using the R package “Limma” (read.maimages, backgroundCorrect, and normalizeBetweenArrays) [17]. DEGs were filtered using the R package “Limma”. The threshold was determined as the adjusted p-value of <0.05 and |log2 fold change| >1.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41127814", "locator": "sections[4] \"Screening of differentially expressed genes (DEGs)\" paragraph 2", "quote": "The raw counts of gene expression data in GSE181549 were normalized using the R package “Limma” (read.maimages, backgroundCorrect, and normalizeBetweenArrays) [17]. DEGs were filtered using the R package “Limma”. The threshold was determined as the adjusted p-value of <0.05 and |log2 fold change| >1."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Data will be made available on request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41127814", "locator": "sections[29] \"Data availability\" paragraph 2", "quote": "Data will be made available on request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "P4HA3 was the sole upregulated gene among collagen-modifying enzymes in SSc.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:41127814", "locator": "sections[16] \"P4HA3 is the sole upregulated gene among collagen-modifying enzymes in SSc\" paragraph 2", "quote": "P4HA3 was the sole upregulated gene among collagen-modifying enzymes in SSc, rather than P4HA1 and P4HA2 (Fig. 1C)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "P4HA3 was the sole upregulated gene among collagen-modifying enzymes in SSc.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:41127814"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "blocked", "blocked_on": "data:accession_absent", "description": "The GEO series accession resolves and its sample accessions are listed. 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DEGs were filtered using the R package “Limma”. 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Immunohistochemistry indicated that P4HA3- and TGF-β1-positive ce"], "order_basis": "paper_text_order:1259", "id": "assay:1"}, {"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["yproline levels were reduced following P4HA3 knockdown in human fibroblasts. Conclusion: Our result", "ydroxyproline. Short interfering RNA (siRNA) transfection was performed to knock down P4HA3 in fibrobl", "ck down P4HA3 in fibroblasts. The cells were transfected with a premix containing siRNA and GP-transf", "was replaced with fresh medium after 48 h of transfection. 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