AbstractAimsMitochondrial dysfunction and inflammation are at the core of axonal degeneration in several multifactorial neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease. The transcriptional coregulator RIP140/NRIP1 (receptor‐interacting protein 140) modulates these functions in liver and adipose tissue, but its role in the nervous system remains unexplored. Here, we investigated the impact of RIP140 in the Abcd1⁻ mouse model of X‐linked adrenoleukodystrophy (X‐ALD), a genetic model of chronic axonopathy involving the convergence of redox imbalance, bioenergetic failure, and chronic inflammation.Methods and resultsWe provide evidence that RIP140 is modulated through a redox‐dependent mechanism driven by very long‐chain fatty acids (VLCFAs), the levels of which are increased in X‐ALD. Genetic inactivation of RIP140 prevented mitochondrial depletion and dysfunction, bioenergetic failure, inflammatory dysregulation, axonal degeneration and associated locomotor disabilities in vivo in X‐ALD mouse models.ConclusionsTogether, these findings show that aberrant overactivation of RIP140 promotes neurodegeneration in X‐ALD, underscoring its potential as a therapeutic target for X‐ALD and other neurodegenerative disorders that present with metabolic and inflammatory dyshomeostasis.