Dietary VLCFA restriction and PPAR-targeted therapies in X-linked adrenoleukodystrophy: A narrative review of emerging clinical evidence

X-linked adrenoleukodystrophy (X-ALD) is a rare peroxisomal disease caused by mutations in the ABCD1 gene, leading to impairment of the β-oxidation of very-long-chain fatty acids (VLCFAs) and progressive neurodegeneration. The clinical presentations vary between childhood cerebral adrenoleukodystrophy and adult adrenomyeloneuropathy. There have been no effective treatment options except in the case of early cerebral disease, where hematopoietic stem-cell transplantation is used. This narrative review synthesizes existing data on dietary VLCFA restriction and new pharmacological approaches to peroxisomal metabolism in X-ALD. To identify key experimental, clinical, and translational studies, a targeted literature search across PubMed, Scopus, and Web of Science identified key studies published between 1989 and 2026 that addressed dietary interventions, peroxisome proliferator-activated receptor (PPAR)-modulating therapies, and clinical outcomes in X-ALD. Dietary interventions, VLCFA-restricted diets, and preparations such as Lorenzo’s oil have also been shown to lower circulating VLCFA levels. They may delay disease progression in presymptomatic patients. Recent pharmacological advances are moving towards PPAR-targeted therapies, where drugs like leriglitazone demonstrate the potential to stabilize neurological progression and improve metabolic profiles in both clinical and translational research. Mechanistic evidence also indicates that modulation of PPAR signaling can affect VLCFA metabolism, mitochondrial activity, and neuroinflammatory processes. Altogether, dietary interventions and PPAR-targeted therapies may serve as complementary approaches in the management of X-ALD. The narrative design and the heterogeneity of the existing research limit the ability to draw definitive conclusions, and larger controlled studies are needed to establish the long-term clinical efficacy and optimize therapeutic strategies.