Exploring the interplay between adipokine-mediated celastrol target genes and T cells in diabetic nephropathy: a mendelian randomization-based causal inference.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:40103004", "kind": "science-record", "revision": 4, "content_hash": "sha256:513b2a5a520fba7016136b6653acbc9db87b6d191f16ec3feb0be25823e6816b", "created_at": "2026-11-01T20:30:18Z", "updated_at": "2026-11-01T22:56:15Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Exploring the interplay between adipokine-mediated celastrol target genes and T cells in diabetic nephropathy: a mendelian randomization-based causal inference.", "doi": "10.1186/s13098-025-01665-0", "pmid": "40103004", "authors": ["Xiaojuan Wang", "Mohamad Hafizi Abu Bakar", "Mohd Asyraf Kassim", "Khairul Anuar Shariff", "Jing Wang", "Manli Xu"], "journal": "Diabetology & metabolic syndrome", "year": 2025, "abstract": "BACKGROUND: Diabetic nephropathy (DN) is influenced by dysregulated adipokines, which play a key role in inflammation, immune responses, and lipid metabolism. However, the precise molecular mechanisms linking adipokine dysregulation, immune cell infiltration, and metabolic reprogramming in DN remain poorly understood. Celastrol, a bioactive lipid regulator, has been shown to mitigate renal immune-inflammatory damage by inhibiting the PI3K/Akt/NF-κB signaling pathway. Yet, its specific impact on adipokine-mediated immune responses and lipid metabolism in DN is unclear. This study aims to elucidate the interplay between adipokine-mediated target genes in DN and investigate how celastrol modulates these interactions.\nMETHODS: Gene expression profiles of DN patients were obtained from GEO datasets (GSE30122 and GSE30528) and analyzed for differentially expressed genes (DEGs) using the limma package. Gene set variation analysis (GSVA) was conducted to assess lipid metabolism pathways, while Mendelian randomization (MR) and Pearson correlation evaluated the association between DEGs and adipokines. Immune cell infiltration was analyzed using the IOBR R package (MCP-counter and xCell methods), followed by MR analysis of DN-related immune responses. Celastrol target genes were identified using the SEA database.\nRESULTS: A total of 70 intersecting DEGs were identified. GSVA revealed that brown and beige adipocyte differentiation pathways were downregulated, while adipocyte-related pathways were upregulated in DN (p < 0.05). MR analysis demonstrated that adiponectin was negatively associated with DN (OR = 0.77, P = 0.005), whereas leptin (OR = 1.92, P = 0.016) and resistin (OR = 1.43, P < 0.001) were positively associated. Three key genes, MAGI2, FGF9, and THBS2 were linked to DN risk and T cell infiltration. THBS2 was positively correlated with T cell infiltration (OR = 0.51, P = 6.7e-06), while FGF9 (OR = -0.8, P = 2.2e-16) and MAGI2 (OR = 0.75, P = 1.3e-13) were negatively correlated. 22 celastrol target genes, including MAGI2, FGF9, and THBS2, were identified.\nCONCLUSION: Our findings reveal that celastrol modulates DN progression through adipokine-immune crosstalk, with FGF9, MAGI2, and THBS2 emerging as key regulatory genes. These insights provide new avenues for biomarker discovery and therapeutic implications in the development of DN.", "claims": [{"id": "claim-method", "statement": "MR analysis was conducted using the TwoSampleMR package with several statistical methods, including Inverse Variance Weighted (IVW), Maximum Likelihood, MR-Egger, Weighted Median, and Weighted Mode, to assess the causal relationship between exposures and the outcome.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40103004", "locator": "sections[6] \"MR analysis\" paragraph 2", "quote": "MR analysis was conducted using the TwoSampleMR package with several statistical methods, including Inverse Variance Weighted (IVW), Maximum Likelihood, MR-Egger, Weighted Median, and Weighted Mode, to assess the causal relationship between exposures and the outcome."}], "state": "complete"}, {"id": "claim-data-access", "statement": "No datasets were generated or analysed during the current study.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40103004", "locator": "sections[25] \"Data availability\" paragraph 2", "quote": "No datasets were generated or analysed during the current study."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Mendelian randomization analysis showed that adiponectin was negatively associated with diabetic nephropathy, whereas leptin and resistin were positively associated with diabetic nephropathy.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:40103004", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "MR analysis demonstrated that adiponectin was negatively associated with DN (OR = 0.77, P = 0.005), whereas leptin (OR = 1.92, P = 0.016) and resistin (OR = 1.43, P < 0.001) were positively associated."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "Mendelian randomization analysis showed that adiponectin was negatively associated with diabetic nephropathy, whereas leptin and resistin were positively associated with diabetic nephropathy.", "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:40103004"], "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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