Molecular endotyping in systemic lupus erythematosus: an integrative framework toward precision therapy
- 1Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences
- 2Department of Medical Laboratory Science, Okayama University Faculty of Health Sciences
Abstract
Systemic lupus erythematosus (SLE) is a clinically defined syndrome arising from heterogeneous and dynamically interacting molecular programs. Recent transcriptomic, single-cell, spatial, and functional studies have identified recurrent molecular states; however, published three-, five-, six-, and eight-group taxonomies are not directly interchangeable. In this review, the published evidence was synthesized within a pragmatic framework of four overlapping candidate programs: interferon/interferon-stimulated gene (IFN/ISG), B cell/plasmablast, neutrophil/neutrophil extracellular trap (NET), and an emerging immunometabolic program. Complement/immune-complex activation is considered a cross-cutting effector axis rather than a mutually exclusive endotype. The molecular endotype is defined operationally, and a distinction is made between pathway signatures, candidate endotypes, and clinically actionable endotypes. In this review, activity biomarkers, prognostic biomarkers, pharmacodynamic biomarkers, and predictive biomarkers are distinguished; the transcriptomic ISG-high states are distinguished from directly measurable type I IFN bioactivity; and the contributions of short-lived plasmablasts and long-lived plasma cells to autoantibody production are also examined. It should be emphasized that endotype assignment is time- and compartment-dependent and that blood signatures may not fully capture organ-specific disease, particularly lupus nephritis. Molecular endotyping in SLE should therefore be viewed as a research framework toward precision therapy rather than as a current treatment algorithm. Prospective biomarker-enriched trials and longitudinal multi-compartment profiling will be required to establish clinically actionable endotypes.
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BibTeX
@article{terajima2026molecular,
title = {{Molecular endotyping in systemic lupus erythematosus: an integrative framework toward precision therapy}},
author = {Yuya Terajima and Yoshinori Matsumoto and Shoichi Nawachi and Yosuke Asano and Keigo Hayashi and Yoshia Miyawaki and Haruki Watanabe and Eri Katsuyama and Takayuki Katsuyama and Jun Wada},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1959612},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1959612/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Molecular endotyping in systemic lupus erythematosus: an integrative framework toward precision therapy
AU - Yuya Terajima
AU - Yoshinori Matsumoto
AU - Shoichi Nawachi
AU - Yosuke Asano
AU - Keigo Hayashi
AU - Yoshia Miyawaki
AU - Haruki Watanabe
AU - Eri Katsuyama
AU - Takayuki Katsuyama
AU - Jun Wada
PY - 2026
DA - 2026/10/19
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1959612
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1959612/full
AB - Systemic lupus erythematosus (SLE) is a clinically defined syndrome arising from heterogeneous and dynamically interacting molecular programs. Recent transcriptomic, single-cell, spatial, and functional studies have identified recurrent molecular states; however, published three-, five-, six-, and eight-group taxonomies are not directly interchangeable. In this review, the published evidence was synthesized within a pragmatic framework of four overlapping candidate programs: interferon/interferon-stimulated gene (IFN/ISG), B cell/plasmablast, neutrophil/neutrophil extracellular trap (NET), and an emerging immunometabolic program. Complement/immune-complex activation is considered a cross-cutting effector axis rather than a mutually exclusive endotype. The molecular endotype is defined operationally, and a distinction is made between pathway signatures, candidate endotypes, and clinically actionable endotypes. In this review, activity biomarkers, prognostic biomarkers, pharmacodynamic biomarkers, and predictive biomarkers are distinguished; the transcriptomic ISG-high states are distinguished from directly measurable type I IFN bioactivity; and the contributions of short-lived plasmablasts and long-lived plasma cells to autoantibody production are also examined. It should be emphasized that endotype assignment is time- and compartment-dependent and that blood signatures may not fully capture organ-specific disease, particularly lupus nephritis. Molecular endotyping in SLE should therefore be viewed as a research framework toward precision therapy rather than as a current treatment algorithm. Prospective biomarker-enriched trials and longitudinal multi-compartment profiling will be required to establish clinically actionable endotypes.
SN - 1664-3224
ER -