Systemic ELOVL6 activity predicts survival and represents a modifiable target of amyotrophic lateral sclerosis

BackgroundAmyotrophic lateral sclerosis (ALS) is characterized by profound metabolic reprogramming, yet the lack of biomarkers for specific druggable targets remains a major hurdle for precision medicine. We hypothesized that peripheral lipid biosynthetic signatures could serve as both prognostic indicators and a roadmap for identifying novel disease-modifying targets. MethodsWe assessed serum fatty acid (FA) metabolic pathways in two independent longitudinal cohorts (n = 37 and n = 38) using high-dimensional CoxBoost modeling. Primary outcomes were survival and functional staging milestones, including non-invasive ventilation and gastrostomy. The biological relevance of the identified candidate was further assessed through correlation with plasma neurofilament light-chain (NfL) levels. Causality and therapeutic potential were validated in Drosophila melanogaster models of TDP-43 proteinopathy via genetic ablation and pharmacological inhibition. ResultsOur multi-parametric model, comprising two clinical variables and the estimated ELOVL6 (elongation of very long-chain fatty acids protein 6) activity, demonstrated robust prognostic accuracy (Unos C 0.69) across both cohorts; ELOVL6 activity served as a strong independent predictor of mortality and functional decline. Notably, high ELOVL6 activity significantly correlated with elevated plasma NfL levels (p < 0.01), linking peripheral elongation imbalances to central axonal damage. In Drosophila, ELOVL6 overactivation was identified as a conserved pathological consequence of TDP-43 dysfunction, characterized by an increased C18:0/C16:0 ratio in both loss-of-function and gain-of-function models. Inhibition of ELOVL6, either genetically or pharmacologically, rescued neuromuscular junction integrity, prolonged survival, and significantly reduced pathological TDP-43 phosphorylation in glial models. ConclusionThese findings position ELOVL6 as a promising modifiable metabolic node with potential for disease-modifying intervention in ALS. Beyond its potential utility for identifying high-risk metabolic profiles and assisting in prognostic counseling, ELOVL6 bridges systemic lipid dysregulation with TDP-43 proteinopathy. Targeting this pathway offers a dual opportunity: as a biological marker to supplement clinical staging and as a druggable enzymatic target to ameliorate motor neuron degeneration. HIGHLIGHTSO_LISystemic ELOVL6 activity is a robust independent predictor of ALS survival. C_LIO_LIHigh ELOVL6 levels correlate with plasma NfL and functional decline. C_LIO_LIInhibition of ELOVL6 rescues NMJ integrity and survival in Drosophila models. C_LIO_LIPharmacological targeting of ELOVL6 reduces glial TDP-43 phosphorylation. C_LIO_LIELOVL6 represents a druggable metabolic node linking lipids to proteinopathy. C_LI