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Excess VLCFA drives impaired cellular functions (e.g. disrupted mitochondrial function), inflammation, and neurodegeneration. Major disease phenotypes include: adrenomyeloneuropathy (AMN), progressive spinal cord axonal degeneration, and cerebral ALD (C\u2010ALD), inflammatory white matter demyelination and degeneration. No pharmacological treatment is available to\u2010date for ALD. Pioglitazone, an anti\u2010diabetic thiazolidinedione, exerts potential benefits in ALD models. Its mechanisms are genomic (PPAR\u03b3 agonism) and nongenomic (mitochondrial pyruvate carrier\u2014MPC, long\u2010chain acyl\u2010CoA synthetase 4\u2014ACSL4, inhibition). However, its use is limited by PPAR\u03b3\u2010driven side effects (e.g. weight gain, edema). PXL065 is a clinical\u2010stage deuterium\u2010stabilized (<jats:italic>R<\/jats:italic>)\u2010enantiomer of pioglitazone which lacks PPAR\u03b3 agonism but retains MPC activity. Here, we show that incubation of ALD patient\u2010derived cells (both AMN and C\u2010ALD) and glial cells from Abcd1\u2010null mice with PXL065 resulted in: normalization of elevated VLCFA, improved mitochondrial function, and attenuated indices of inflammation. Compensatory peroxisomal transporter gene expression was also induced. Additionally, chronic treatment of Abcd1\u2010null mice lowered VLCFA in plasma, brain and spinal cord and improved both neural histology (sciatic nerve) and neurobehavioral test performance. Several in vivo effects of PXL065 exceeded those achieved with pioglitazone. PXL065 was confirmed to lack PPAR\u03b3 agonism but retained ACSL4 activity of pioglitazone. PXL065 has novel actions and mechanisms and exhibits a range of potential benefits in ALD models; further testing of this molecule in ALD patients is warranted.<\/jats:p>","DOI":"10.1002\/jimd.12510","type":"journal-article","created":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T12:05:28Z","timestamp":1651752328000},"page":"832-847","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Therapeutic potential of deuterium\u2010stabilized (<i>R<\/i>)\u2010pioglitazone\u2014<scp>PXL065<\/scp>\u2014for X\u2010linked adrenoleukodystrophy"],"prefix":"10.1002","volume":"45","author":[{"given":"Pierre\u2010Axel","family":"Monternier","sequence":"first","affiliation":[{"name":"Poxel SA  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaspreet","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Neurology Henry Ford Health System  Detroit Michigan 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