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Historically, management relied on renin\u2013angiotensin system inhibition and empirical immunosuppression, yet high lifetime kidney failure risk persists despite optimized care. This review synthesizes advances in molecular pathogenesis, highlighting how the traditional multi\u2010hit hypothesis\u2014while foundational for targeted therapy development\u2014fails to capture IgAN's recurrent, self\u2010amplifying nature. We introduce the \u201cspiral hypothesis\u201d as a dynamic model of cyclical immune\u2010injury cascades, better explaining disease chronicity and necessitating sustained maintenance therapy. Emerging targeted therapies\u2014including B\u2010cell targeted agents (e.g., APRIL\/BAFF inhibitors), complement inhibitors (e.g., iptacopan), and mucosal immunomodulators (e.g., TRF\u2010budesonide)\u2014enable early intervention addressing both upstream immunological drivers and downstream fibrotic pathways. We critically evaluate treat\u2010to\u2010target frameworks, defining remission endpoints (proteinuria &lt;0.3\u00a0g\/day, hematuria resolution, estimated glomerular filtration rate slope &lt;\u22121\u00a0mL\/min\/year) and emphasizing biomarker\u2010guided personalization. The paradigm shift toward proactive management prioritizes individualized therapeutic sequencing of novel agents based on dynamic risk stratification. Future priorities include optimizing protocols for high\u2010risk phenotypes and refining long\u2010term safety monitoring to ensure sustainable efficacy.<\/jats:p>","DOI":"10.1002\/mco2.70382","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T07:32:05Z","timestamp":1757316725000},"source":"Crossref","is-referenced-by-count":10,"title":["Immunoglobulin A Nephropathy: Molecular Pathogenesis and Targeted Therapy"],"prefix":"10.1002","volume":"6","author":[{"given":"Xu\u2010Jie","family":"Zhou","sequence":"first","affiliation":[{"name":"Renal Division Kidney Genetics Center Key Laboratory of Renal Disease National Health Commission Peking University First Hospital Peking University Institute of Nephrology Peking University Institute of Nephrology Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University) Ministry of Education, and State Key Laboratory of Vascular Homeostasis and Remodeling Peking University  Beijing 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