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.
4 affiliations
- 1Department of Nephrology, Tianshui the Second People's Hospital, Tianshui Cooperation of Chinese and Western Medicine Hospital, Tianshui City, Gansu Province, China.
- 2Department of Operating Room, Huai'an Hospital of Huai'an City (Huai'an Clinical Medical College of Jiangsu University), Huai'an City, Jiangsu Province, China.
- 3Department of Laboratory, Tianshui the Second People's Hospital, Tianshui Cooperation of Chinese and Western Medicine Hospital, Tianshui City, Gansu Province, China.
- 4Department of Hemodialysis Center, Huzhou Wuxing Hospital of Traditional Chinese and Western Medicine, Huzhou City, Zhejiang Province, China.
Abstract
Background
Membranous 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
Three 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
Across 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
MN 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.
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BibTeX
@article{mao2026donoraware,
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.}},
author = {Yalan Mao and Ran Li and Bin Li and Hongfen Pan},
journal = {Frontiers in genetics},
year = {2026},
month = oct,
doi = {10.3389/fgene.2026.1916595},
url = {https://europepmc.org/article/MED/42948845},
note = {CC BY},
}
RIS
TY - JOUR
TI - 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.
AU - Yalan Mao
AU - Ran Li
AU - Bin Li
AU - Hongfen Pan
PY - 2026
DA - 2026/10/14
JO - Frontiers in genetics
DO - 10.3389/fgene.2026.1916595
UR - https://europepmc.org/article/MED/42948845
AB - Background Membranous 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 Three 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 Across 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 MN 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.
SN - 1664-8021
ER -