Nervonic acid supplementation mitigates disease severity biomarkers in adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a severe neurometabolic disorder caused by mutations in the ABCD1 gene, leading to impaired peroxisomal β-oxidation of very long-chain fatty acids (VLCFAs). The accumulation of saturated VLCFAs, predominantly C26:0, in plasma and across all tissues, contributes to adrenal dysfunction and progressive neurodegeneration. No approved therapy addresses the diverse spectrum of ALD manifestations, underscoring the urgent need for safe, accessible, and preventive treatments. Nervonic acid (NA), a monounsaturated fatty acid, is potentially beneficial for ALD through its neuroprotective effects. Here, we report the safety and therapeutic efficacy of NA in a 4-week dietary intervention study using a mouse model of ALD. NA treatment significantly decreased plasma C26:0-lysophosphatidylcholine, a diagnostic and disease-severity biomarker of ALD, by about 60% as early as one week after intervention. After 4-week treatment, NA markedly reduced free C26:0 and total saturated VLCFA levels in plasma and tissues. Moreover, we observed approximately 56% reduction in brain C26:0-lysophosphatidylcholine levels in NA-fed mice, an effect not reported with other drug intervention. Through comparative microbiome analysis, we show for the first time distinct baseline differences between ALD and wild-type mice, with dietary fatty acid supplementation preventing further dysbiosis. No adverse effects on body weight or food intake were observed throughout the study. Overall, this is the first report demonstrating that an oral dietary fatty acid can ameliorate the hallmark biochemical abnormalities of ALD in plasma and brain, highlighting its potential as a safe and effective therapy, particularly for presymptomatic individuals carrying this genetic defect.