{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:09:42Z","timestamp":1788952182478,"version":"build-2803163510"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The complement system is increasingly recognized as a contributor to the pathogenesis of focal segmental glomerulosclerosis (FSGS). However, a comprehensive, tissue-based characterization of complement dysregulation in human FSGS kidneys remains lacking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed an integrative multi-omics analysis combined with histological validation. Proteomic (LC-MS\/MS) profiling was conducted on renal cortical tissues from 11 patients with FSGS and 12 healthy controls from our institution, while transcriptomic (RNA-seq) analysis was performed using publicly available datasets comprising 100 FSGS and 30 normal samples.\n                      <jats:italic>In situ<\/jats:italic>\n                      deposition of key complement components (C1q, C3c, C5a, C7, CFB, CFH, MBL) was assessed using multiplex immunofluorescence confocal microscopy. Correlations between complement deposition and clinical outcomes were analyzed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Multi-omics analyses consistently identified the complement and coagulation cascades among the most significantly enriched pathways in FSGS. Transcriptomic data revealed upregulation of C1QB, C1R, C1S, C2, C3, and CFB mRNA, whereas proteomic profiling showed upregulation of C4BPA, C5, C8B, C8G, and CFHR5, along with downregulation of C1R, C1S, C2, CFB, and CFH. In Tmem30a knocked down mouse podocytes, complement pathway enrichment was observed, but core components including C3, C1r, C1s, and CFB were downregulated. Immunofluorescence confirmed frequent glomerular C3c deposition (43.75%), with lower positivity rates for C1q (15.63%), CFB (12.5%), and CFH (12.5%); MBL deposition was rare. Patients with glomerular deposition of C3c, C1q, CFB, or CFH exhibited significantly lower probabilities of achieving complete remission.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study systematically demonstrates concurrent dysregulation of the classical and alternative complement pathways in FSGS. The deposition of specific complement components in renal tissue strongly correlates with disease activity, treatment resistance, and poor prognosis, suggesting their potential as pathological biomarkers and therapeutic targets. These findings enhance the understanding of FSGS immunopathogenesis and support the strategy of complement-targeted therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1852918","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:14:02Z","timestamp":1788948842000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics analyses demonstrate complement dysregulation is involved in focal segmental glomerulosclerosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Yingxue","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Nephrology, Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Clinical Research Center for Kidney Diseases","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sipei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Clinical Research Center for Kidney Diseases","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institutes for Systems Genetics, West China Hospital, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Clinical Research Center for Kidney Diseases","place":["Chengdu, 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