{ "abstract": "Background\n\nMembranous nephropathy (MN) is an immune-mediated glomerular disease in which sustained proteinuria exposes renal tubular epithelial cells to an abnormal filtered-protein load. The tubular metabolic response to this exposure remains incompletely characterized. We investigated whether MN is associated with a reproducible tubular cholesterol-handling transcriptional state and assessed its relationship to protein overload in vitro. We further evaluated whether an experimentally anchored five-gene subset showed a coordinated tumor-associated transcriptional shift across major renal cancer histologies.Methods\n\nThree kidney single-cell RNA-sequencing datasets and one glomerular bulk-transcriptomic cohort were analyzed using the donor as the biological replicate. GSE241302 was used for complete-case exploratory discovery, OEP004186 for formal donor-aware support, GSE171458 for directional support, and GSE200828 for tissue-level disease context. A frozen 47-gene LXR-linked cholesterol-handling program and its nested 37-gene cholesterol transport/efflux component were evaluated by donor-level pseudobulk analysis, leave-one-donor-out and leave-one-gene-out sensitivity analyses. HK-2 cells were exposed to protein overload, followed by quantitative reverse-transcription PCR for representative transport and lipid-remodeling genes. The same experimentally anchored five-gene panel was then evaluated in 129 paired tumor-adjacent-normal samples across TCGA-KIRC, TCGA-KIRP, and TCGA-KICH to define a renal tumor-associated lipid-remodeling context.Results\n\nAcross all 3 MN donors in GSE241302, program scores were higher than the internal reference in proximal tubule (PT) and loop-of-Henle/thick ascending limb (loop/TAL) compartments. In OEP004186, the program was increased in PT (effect +0.480, false-discovery rate [FDR] 0.0128), PT-VCAM1 (+0.348, FDR 0.0165), and loop/distal epithelial cells (+0.310, FDR 0.0242), with positive effects in every leave-one-MN-donor-out analysis. GSE171458 provided concordant directional support in PT and loop/TAL. The PT-VCAM1 fraction was not increased in MN, whereas the program remained higher within both PT and PT-VCAM1, favoring a within-state transcriptional change. Sixteen program genes showed positive average effects across the three single-cell resources. In GSE200828, the overall program was higher in MN than in living donors (+0.226, FDR 0.0349) but not higher than in other glomerular diseases. Protein overload increased ABCA1, ABCG1, SREBF1, FASN, and SCD expression in HK-2 cells. Across the three renal cancer histologies, the five-gene panel showed a concordant paired increase (REML-pooled effect +0.967, 95% CI 0.843-1.092), and 85.3% of patients exhibited simultaneous increases in the cholesterol-efflux and lipid-synthesis/remodeling arms.Conclusion\n\nMN is associated with a donor-supported LXR-linked cholesterol-handling transcriptional state concentrated in PT and loop/TAL-related epithelial compartments. The state is responsive to protein overload in HK-2 cells and may reflect a broader tubular lipid-homeostasis response to proteinuric kidney injury. The data do not establish direct LXR activation, increased cholesterol-efflux flux, or MN specificity. The paired renal cancer analysis further identifies a coordinated tumor-associated five-gene lipid-remodeling signature across KIRC, KIRP, and KICH, while not establishing tumor-cell-intrinsic LXR activation, immune effects, or a causal tumor mechanism.", "abstract_shown": true, "affiliations": [ "Department of Nephrology, Tianshui the Second People's Hospital, Tianshui Cooperation of Chinese and Western Medicine Hospital, Tianshui City, Gansu Province, China.", "Department of Operating Room, Huai'an Hospital of Huai'an City (Huai'an Clinical Medical College of Jiangsu University), Huai'an City, Jiangsu Province, China.", "Department of Laboratory, Tianshui the Second People's Hospital, Tianshui Cooperation of Chinese and Western Medicine Hospital, Tianshui City, Gansu Province, China.", "Department of Hemodialysis Center, Huzhou Wuxing Hospital of Traditional Chinese and Western Medicine, Huzhou City, Zhejiang Province, China." ], "article_type": "research article", "arxiv": null, "author_total": 4, "authors": [ { "affs": [ 0 ], "name": "Yalan Mao" }, { "affs": [ 1 ], "name": "Ran Li" }, { "affs": [ 2 ], "name": "Bin Li" }, { "affs": [ 3 ], "name": "Hongfen Pan" } ], "bibtex": "https://research.draconitic.com/paper/ewd656rjx47b1.bib", "cited_by": 0, "doi": "10.3389/fgene.2026.1916595", "fulltext_url": "https://europepmc.org/articles/PMC13713173", "id": "ewd656rjx47b1", "issns": [ "1664-8021" ], "landing_url": "https://europepmc.org/article/MED/42948845", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Original Research" ], [ "openalex", "2727|Renal Diseases and Glomerulopathies" ] ], "openalex": "W7221597313", "pdf_url": "https://europepmc.org/articles/PMC13713173?pdf=render", "pmcid": "PMC13713173", "pmid": "42948845", "published": "2026-10-14", "publisher": "Frontiers Media SA", "ris": "https://research.draconitic.com/paper/ewd656rjx47b1.ris", "sources": [ { "first_seen": "2026-10-31T00:20:34Z", "native_id": "MED:42948845", "source": "europepmc", "url": "https://europepmc.org/article/MED/42948845" }, { "first_seen": "2026-10-31T12:23:34Z", "native_id": "PMC13713173", "source": "pmc", "url": "https://doi.org/10.3389/fgene.2026.1916595" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2727|Renal Diseases and Glomerulopathies", "subfield": "general" } ], "title": "Donor-aware multi-cohort single-cell analysis identifies an LXR-linked tubular cholesterol-handling state in membranous nephropathy with a coordinated five-gene lipid-remodeling signature across renal tumors.", "title_text": "Donor-aware multi-cohort single-cell analysis identifies an LXR-linked tubular cholesterol-handling state in membranous nephropathy with a coordinated five-gene lipid-remodeling signature across renal tumors.", "type": "peer-reviewed", "updated_at": "2026-10-31T12:23:34Z", "url": "https://research.draconitic.com/paper/ewd656rjx47b1", "venue": "Frontiers in genetics", "versions": [] }