2026-08-15 | From Common Pathway to Divergent Diseases: Metabolic Aspects of Inborn Errors of CoA Biosynthesis.

Coenzyme A (CoA) biosynthesis is a conserved, dynamically regulated pathway essential for mitochondrial energy production, fatty acid oxidation, lipid biosynthesis and protein acylation. Biallelic variants in PANK2, PPCS, PPCDC, and COASY cause rare inborn errors of CoA biosynthesis, associated with markedly different clinical phenotypes: PANK2 and COASY defects predominantly cause neurological disorders within or adjacent to the neurodegeneration with brain iron accumulation (NBIA) spectrum, whereas PPCS and PPCDC deficiencies present mainly as severe early-onset dilated cardiomyopathy. However, COASY variants can also cause pontocerebellar hypoplasia and riboflavin-responsive lipid storage myopathy. This review examines these four disorders from a metabolic perspective, integrating clinical features, experimental models, biochemical data and emerging therapeutic approaches. Current evidence indicates that disease pathogenesis cannot be explained only by global CoA depletion. Total CoA levels may be reduced in PPCS and PPCDC deficiency, but are often preserved under basal conditions in PKAN and COASY-related models. Instead, impaired compartment-specific CoA handling and failure to sustain CoA-dependent flux under increased metabolic demand are emerging as central pathogenic concepts. Perturbation of fatty acid handling, acyl-CoA/acylcarnitine balance, mitochondrial function, iron homeostasis, protein acylation and 4'-phosphopantetheinylation may contribute to tissue-selective vulnerability. Therapeutic strategies are therefore likely to require disease-specific approaches, including precursor bypass or PANK activation where pathway flux can be restored, early pantethine supplementation in cardiomyopathic forms, and downstream or gene-directed strategies for COASY-related disorders. Understanding CoA as a regulator of metabolic adaptability provides a unifying framework for interpreting both shared mechanisms and disease divergence.

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2026-08-12 | Modelling Ferroptosis in a Human Microglial Line by Sequential Exposure to Iron and GPX4 Inhibition.

Excessive iron accumulation is a pathological feature of several neurodegenerative diseases (NDDs), and a growing body of evidence suggests that ferroptosis, an iron-dependent form of regulated cell death (RCD) driven by lipid peroxidation, is implicated in their pathogenesis. Microglia, the brain's resident immune cells, buffer iron overload but become susceptible to ferroptotic death, exacerbating neuroinflammation and neuronal loss. To uncover the molecular events leading to microglial ferroptosis, we established a human microglial ferroptosis model using the HMC3 cell line. This model recapitulates core features of ferroptosis, including increased reactive oxygen species (ROS) and peroxidation of lipids at the membrane, both rescued by ferrostatin-1 (Fer-1). We used this model to perform integrated multiomic profiling and identified significant dysregulation in lipid species, notably an accumulation of sterols, including oxysterols such as 7-oxo-cholesterol, alongside the oxidation of polyunsaturated fatty acids (PUFAs) that are characteristic of ferroptosis. Transcriptomic and proteomic analyses corroborate these findings, revealing the upregulation of the mevalonate pathway and cholesterol metabolism. Importantly, the increased expression of some of these key metabolic genes was also reversed by Fer-1 treatment, indicating their role in a preferroptotic signature. Our model provides a novel platform for investigating early molecular events in microglia ferroptosis. Integrating these findings into future investigations could uncover new protective mechanisms against microglial ferroptosis to ensure homeostatic regulation of ROS levels and sterol metabolism.

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2026-08-03 | In Silico Characterization of a Novel Sulfonamide Derivative as a GPX4 Inhibitor: Docking, ADME, and Toxicity Evaluation to Deliver a Translatable Pharmacophore for Wet-Lab Research

Ferroptosis an iron-dependent, regulated form of cell death driven by the lethal accumulation of lipid hydroperoxides within cellular membranes is suppressed principally by glutathione peroxidase 4 (GPX4), a selenoenzyme whose inhibition has emerged as a strategy of growing therapeutic interest in both oncology and neurodegeneration. Despite this promise, the existing GPX4 inhibitor landscape is dominated by covalent electrophiles that carry well-documented pharmacokinetic liabilities, underscoring the need for drug-like, non-covalent alternatives. To address this gap, an integrated computational workflow was applied to a newly designed sulfonamide derivative (hereafter the target compound). Structure-based molecular docking with AutoDock Vina returned a top-ranked binding affinity of −4.67 kcal mol-1; interaction analysis identified a bifurcated hydrogen-bonding network anchoring the ligand to Thr 132 (2.01 Å) and Gln 70 (2.67 Å), complemented by hydrophobic contacts with Phe 71, Asn 102, Ala 126, and Ile 127. Pharmacokinetic profiling via SwissADME confirmed compliance with Lipinski's Rule of Five (MW = 324.37 g mol-1, LogP = 1.63, zero violations), high gastrointestinal absorption, blood–brain barrier (BBB) permeability as assessed by the BOILED-Egg model, zero PAINS alerts, and a synthetic accessibility score of 3.05. Toxicological assessment through ProTox-3.0 estimated an acute oral LD50 of 5000 mg kg-1 (GHS Class 5) with predicted inactivity across hepatotoxicity, cardiotoxicity, nephrotoxicity, mutagenicity, carcinogenicity, and cytotoxicity endpoints. These findings collectively indicate that the target compound satisfies binding, drug-likeness, and safety requirements simultaneously, positioning it as a viable lead candidate for experimental follow-up.

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2026-07-29 | Supplementation via DAF-16 and pnk-1 driven pantothenate-coenzyme A flux improves disease related stress resistance in C. elegans.

Metabolic pathways are increasingly recognized as tractable targets in aging and disease. Building on prior work demonstrating that supplementation with low-molecular weight metabolites (amino acids, vitamins, and their intermediates) can extend lifespan in Caenorhabditis elegans, we focused on pantothenate (vitamin B5), which is dysregulated in sarcopenic muscle and in several neurodegenerative and metabolic disorders. Pantothenate is the obligate precursor of coenzyme A through a short, highly conserved biosynthetic pathway in which loss-of-function mutations can cause neurodegeneration with brain iron accumulation. In C. elegans, the longevity curtailing transcription factor DAF-16/FOXO has a conserved binding element in the promoter region of pnk-1, encoding the first enzyme (PNK-1) in the coenzyme A pathway, and pnk-1 is markedly upregulated in long-lived daf-2 (insulin/-like receptor) mutants, implicating coenzyme A metabolism in longevity. Here, we demonstrate that CoA levels naturally increase during early life and decrease towards older age in C. elegans. Dietary pantothenate supplementation increases coenzyme A levels with minimal effects on lifespan but systemic effects on lipid metabolism, mitochondrial dynamics, and muscle structure under basal conditions. Under DAF-16-associated stress conditions, including heat and oxidative stress, pnk-1 expression is upregulated and pantothenate supplementation robustly extends lifespan and improves mobility. Finally, we demonstrate dysregulation of daf-16 and pnk-1 expression in amyotrophic lateral sclerosis (ALS) models, in which pantothenate supplementation confers both lifespan extension and cholinergic neuroprotection.

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2026-07-10 | Therapeutic Advances in Major NBIA Disorders: Current Strategies and Translational Challenges

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of rare genetic movement disorders characterized by progressive neurological deterioration, dystonia, parkinsonism, spasticity, and abnormal iron deposition in the basal ganglia. Although iron accumulation is the shared neuroradiological hallmark, most NBIA genes do not directly regulate iron metabolism. Instead, major NBIA forms arise from disruption of distinct but converging cellular pathways, including coenzyme A (CoA) biosynthesis, lipid metabolism, mitochondrial function, and autophagy. This narrative review aims to examine the pathogenic mechanisms of major NBIA disorders, namely pantothenate kinase-associated neurodegeneration (PKAN), COASY protein-associated neurodegeneration (CoPAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN), and beta-propeller protein-associated neurodegeneration (BPAN), and how these insights are guiding therapeutic development. Preclinical strategies aimed at restoring CoA metabolism, improving mitochondrial function, limiting lipid peroxidation, modulating autophagy, or correcting the underlying genetic defect have shown encouraging results, although none have yet reached robust clinical validation. Clinical translation remains limited by disease rarity, clinical heterogeneity, absence of validated biomarkers, and preclinical models that only partially recapitulate human pathology. Advancing the field will depend on earlier molecular diagnosis, biomarkers capable of tracking disease stage, and trial designs suited to ultra-rare populations. NBIA thus offers a paradigm for how mechanistic classification of a genetically defined disease group can redirect therapeutic strategy away from a shared radiological feature and toward pathway-specific intervention.

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