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This requires the presence of efficient glyoxylate detoxification systems in multiple subcellular compartments, as glyoxylate is produced in peroxisomes, mitochondria, and the cytosol. Alanine glyoxylate aminotransferase (AGT) and glyoxylate reductase\/hydroxypyruvate reductase (GRHPR) are the key enzymes involved in glyoxylate detoxification. Bi\u2010allelic mutations in the genes coding for these enzymes cause primary hyperoxaluria type 1 (PH1) and 2 (PH2), respectively. Glyoxylate is derived from various sources, including 4\u2010hydroxyproline, which is degraded in mitochondria, generating pyruvate and glyoxylate, as catalyzed by the mitochondrial enzyme 4\u2010hydroxy\u20102\u2010oxoglutarate aldolase (HOGA); however, counterintuitively, a defect in <jats:italic>HOGA1<\/jats:italic> is the molecular basis of primary hyperoxaluria type 3 (PH3). Irrespective of its underlying cause, hyperoxaluria in humans leads to nephrocalcinosis, recurrent urolithiasis, and kidney damage, which may culminate in kidney failure requiring combined liver\u2010kidney transplantation in severely affected patients. In the past few years, therapeutic options, especially for primary hyperoxaluria type 1 (PH1), have greatly been improved thanks to the introduction of two RNAi\u2010based therapies that inhibit either the production of glycolate oxidase (lumasiran) or lactate dehydrogenase (nedosiran). While lumasiran only targets PH1 patients, nedosiran was specifically developed to target all three subtypes of PH. Inspired by the findings reported in the literature that nedosiran effectively reduced urinary oxalate excretion in PH1 patients but not in PH2 or PH3 patients, we have now revisited glyoxylate metabolism in humans and performed a thorough literature study which revealed that glyoxylate\/oxalate metabolism is not confined to the liver but instead involves multiple different organs. This new view on glyoxylate\/oxalate metabolism in humans may well explain the disappointing results of nedosiran in PH2 and PH3, and provides new clues for the future generation of new therapeutic strategies for PH2 and PH3.<\/jats:p>","DOI":"10.1002\/jimd.12817","type":"journal-article","created":{"date-parts":[[2024,11,24]],"date-time":"2024-11-24T23:39:15Z","timestamp":1732491555000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Human glyoxylate metabolism revisited: New insights pointing to multi\u2010organ involvement with implications for <scp>siRNA<\/scp>\u2010based therapies in primary hyperoxaluria"],"prefix":"10.1002","volume":"48","author":[{"given":"Ronald J. 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Tenerife Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6185-2616","authenticated-orcid":false,"given":"Sander F.","family":"Garrelfs","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology Emma Children's Hospital  Amsterdam The 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