{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:47:03Z","timestamp":1785757623157,"version":"3.56.0"},"reference-count":104,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"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. Med."],"abstract":"<jats:p>IgA nephropathy (IgAN) is an established autoimmune glomerular disease driven by mucosal tolerance failure, aberrant IgA1 glycosylation, and anti-glycan autoantibody formation. Mesangial deposition of galactose-deficient IgA1 (Gd-IgA1) complexes remains the central pathogenic event, though Gd-IgA1 alone is insufficient for disease, and emerging evidence implicates IgA2 deposition as an additional contributor. This review first outlines the classical, lectin, and alternative complement pathways and their predominant activation and regulatory mechanisms in IgAN, clarifying that the alternative pathway can initiate activation independently of the lectin pathway rather than acting solely as its amplifier. We then propose a compartment-based framework linking mesangial complement activation, endothelial and leukocyte responses, podocyte injury, and tubulointerstitial exposure to proteinuria, glomerulosclerosis, and fibrosis, while distinguishing complement-dependent mechanisms from complement-independent injury pathways at each site. We examine how complement biomarkers correspond to specific Oxford MEST-C lesions and discuss the current limitations of integrating these readouts with histology for risk stratification. Finally, we review pathway-selective therapies targeting mannan-binding lectin-associated serine protease (MASP)-2, factor B, C5aR, and C5, emphasizing that complement inhibition should complement rather than replace optimized supportive care and upstream IgA-axis modulation. This integrated view of autoimmune pathogenesis, complement biology, and pathway-selective therapeutics provides a foundation for precision-medicine approaches to progressive IgAN.<\/jats:p>","DOI":"10.3389\/fmed.2026.1896069","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:10:16Z","timestamp":1785755416000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Breaking tolerance in the glomerulus: complement as a driver and therapeutic target in IgA nephropathy"],"prefix":"10.3389","volume":"13","author":[{"given":"Chien-Lin","family":"Lu","sequence":"first","affiliation":[{"name":"School of Medicine, College of Medicine, Fu Jen Catholic University","place":["New Taipei City, Taiwan"]},{"name":"Division of Nephrology, Department of Internal Medicine, Fu Jen Catholic University Hospital, Fu Jen Catholic University","place":["New Taipei City, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Chi","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Taoyuan Armed Forces General Hospital","place":["Taoyuan, Taiwan"]},{"name":"Division of Cardiovascular, Tri-Service General Hospital, National Defense Medical University","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Chao","family":"Wu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Microbiology and Immunology, National Defense Medical University","place":["Taipei, Taiwan"]},{"name":"Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo-Cheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Fu Jen Catholic University Hospital, Fu Jen Catholic University","place":["New Taipei City, Taiwan"]},{"name":"Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation","place":["New Taipei City, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"151564","DOI":"10.1016\/j.semnephrol.2025.151564","article-title":"IgA nephropathy: epidemiology and disease risk across the world","volume":"44","author":"Ghaddar","year":"2024","journal-title":"Semin Nephrol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1681\/ASN.2011050464","article-title":"The pathophysiology of IgA nephropathy","volume":"22","author":"Suzuki","year":"2011","journal-title":"J Am Soc 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