Decoding molecular heterogeneity in lupus nephritis: integrating single-cell and spatial multi-omics for endotype-driven precision therapeutics
- 1Department of Traditional Chinese Medicine, Jiangxi University of Chinese Medicine
- 2Department of Traditional Chinese Medicine, Gaoxin Branch of the First Affiliated Hospital, Nanchang University
Abstract
Lupus nephritis (LN) develops in 40–60% of patients with systemic lupus erythematosus (SLE) and remains the leading cause of renal morbidity and progression to end-stage renal disease (ESRD). While the upstream immunological events initiating LN—including loss of self-tolerance, pathogenic autoantibody production, glomerular immune complex deposition, and type I interferon (IFN) activation—are broadly shared, accumulating evidence demonstrates that these convergent triggers give rise to molecularly heterogeneous tissue injury programs at the renal level. This fundamental divergence provides a mechanistic explanation for the inconsistent therapeutic responses observed with standardized immunosuppressive protocols. Advances in single-cell transcriptomics, spatial gene expression mapping, CITE-seq, and cross-platform multi-omic integration have deconvolved this heterogeneity into at least five recognizable tissue-level injury programs: (i) an IFN-γ-polarized macrophage–tubular epithelial cell co-activation circuit, (ii) a Tfh–B cell ectopic germinal center pathway, (iii) a neutrophil extracellular trap (NET)-driven inflammatory cascade, (iv) a podocyte-autonomous injury program, and (v) a TREM2+ macrophage-orchestrated fibrotic program. Concurrently, multiplexed urinary biomarker platforms are under development as non-invasive surrogates for tissue-level pathogenic activity. This review synthesizes current understanding of disease mechanisms, molecular profiling evidence, biomarker candidates, and mechanism-directed therapies corresponding to each tissue injury program. We map existing and investigational agents—including anifrolumab, obinutuzumab, voclosporin, CAR-T cell therapy, and complement inhibitors—to their mechanistic targets and delineate the design requirements for prospective biomarker-stratified trials essential to validating molecularly guided treatment selection.
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BibTeX
@article{zhou2026decoding,
title = {{Decoding molecular heterogeneity in lupus nephritis: integrating single-cell and spatial multi-omics for endotype-driven precision therapeutics}},
author = {Jun Zhou and Wei Xiao and Hui Jian},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1987126},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1987126/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Decoding molecular heterogeneity in lupus nephritis: integrating single-cell and spatial multi-omics for endotype-driven precision therapeutics
AU - Jun Zhou
AU - Wei Xiao
AU - Hui Jian
PY - 2026
DA - 2026/10/14
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1987126
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1987126/full
AB - Lupus nephritis (LN) develops in 40–60% of patients with systemic lupus erythematosus (SLE) and remains the leading cause of renal morbidity and progression to end-stage renal disease (ESRD). While the upstream immunological events initiating LN—including loss of self-tolerance, pathogenic autoantibody production, glomerular immune complex deposition, and type I interferon (IFN) activation—are broadly shared, accumulating evidence demonstrates that these convergent triggers give rise to molecularly heterogeneous tissue injury programs at the renal level. This fundamental divergence provides a mechanistic explanation for the inconsistent therapeutic responses observed with standardized immunosuppressive protocols. Advances in single-cell transcriptomics, spatial gene expression mapping, CITE-seq, and cross-platform multi-omic integration have deconvolved this heterogeneity into at least five recognizable tissue-level injury programs: (i) an IFN-γ-polarized macrophage–tubular epithelial cell co-activation circuit, (ii) a Tfh–B cell ectopic germinal center pathway, (iii) a neutrophil extracellular trap (NET)-driven inflammatory cascade, (iv) a podocyte-autonomous injury program, and (v) a TREM2+ macrophage-orchestrated fibrotic program. Concurrently, multiplexed urinary biomarker platforms are under development as non-invasive surrogates for tissue-level pathogenic activity. This review synthesizes current understanding of disease mechanisms, molecular profiling evidence, biomarker candidates, and mechanism-directed therapies corresponding to each tissue injury program. We map existing and investigational agents—including anifrolumab, obinutuzumab, voclosporin, CAR-T cell therapy, and complement inhibitors—to their mechanistic targets and delineate the design requirements for prospective biomarker-stratified trials essential to validating molecularly guided treatment selection.
SN - 1664-3224
ER -