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In this study, we observed a negative correlation between fumarate hydratase (FH) expression and the degree of renal fibrosis. Loss of FH function was associated with heightened inflammation and exacerbated tubulointerstitial damage in the kidney. Moreover, FH deficiency aggravated fibrosis in both the liver and lungs. Mechanistically, the depletion of FH in renal tubular cells led to fumarate accumulation. Fumarate directly succinated A-kinase anchoring protein 12 at cysteine 670, thereby diminishing its capacity to inhibit the activity of protein kinase C\u03b6 (PKC\u03b6). This process exacerbated renal inflammation and fibrosis by activating the downstream PKC\u03b6\/NF-\u03baB and PKC\u03b6\/\u03b2-catenin pathways. Additionally, the upregulation of FH through adeno-associated virus 2\/9\u2013mediated FH overexpression markedly mitigated renal inflammation and fibrosis. These findings highlighted the important role of fumarate accumulation in the advancement of renal fibrosis, supporting FH as a potential therapeutic target in renal fibrosis.<\/jats:p>","DOI":"10.1172\/jci200755","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T18:18:11Z","timestamp":1782843491000},"source":"Crossref","is-referenced-by-count":0,"title":["Fumarate-induced succination of A-kinase anchor protein 12 exacerbates renal inflammation and fibrosis"],"prefix":"10.1172","volume":"136","author":[{"given":"Shuai","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Urology, The Fifth Affiliated Hospital of Anhui Medical University, Fuyang, China."},{"name":"Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China."},{"name":"Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Institute of 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