2026-07-14 | Citrulline drives age-related lipid deposition for healthspan

Too much or too less lipid deposition increases mortality, while in contrast, modest lipid deposition during aging is crucial for healthspan. How animals determine the aging state and then promote appropriate lipid deposition for lifespan benefits are largely unknown. In this study, we identified citrulline as a key metabolite driving aging-related lipid deposition for healthspan in Caenorhabditis elegans. Citrulline deficiency reduced aging-related lipid accumulation and shortened lifespan, an effect reversible by dietary supplementation. Mechanistically, during aging, the transcription factor MXL-3 is activated to upregulate the expression of pyr-1, encoding ornithine transcarbamylase (OTC), for the production of citrulline, which then activates the lipogenic enzymes DGAT-2 and MBOA-2 to consequently promote lipid synthesis and deposition for lifespan extension. Collectively, we uncover a MXL-3-citrulline-lipogensis axis to ensure healthspan, providing distinct insights into metabolic aging. Modest lipid deposition during aging benefits healthspan. Li et al reported that aging activates transcription factor MXL-3, which triggers citrulline biosynthesis to promote lipogenesis for lipid deposition, thereby driving healthspan.

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2026-07-10 | Functional Editing of the OTC locus by Targeted Integration with Phenotype Correction and Restoration of Physiological Patterns of Expression.

Here we report highly efficient functional repair of the ornithine transcarbamylase (OTC) locus in mutant mouse and human hepatocytes in vivo using a dual AAV system delivering CRISPR-Cas9 editing reagents and a promoterless donor for targeted integration. The approach was mutation agnostic and targeted intronic sequences to prevent inadvertent inactivation of hypomorphic alleles. Notably, in a murine model, we corrected the metabolic defect and simultaneously achieved liver-wide restoration of physiological metabolic zonation of Otc expression by capturing native cis-acting regulatory elements. The effectiveness of this approach was confirmed using a universally configured therapeutic cassette in patient-derived primary human hepatocytes in vivo. These data provide a powerful template to guide further optimization of this approach and, given the high editing efficacy required for phenotypic effect in OTC deficiency, have broader relevance to other liver disease phenotypes.

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2026-05-29 | Rewriting hepatic fate: emerging gene therapy strategies for liver disease

Several anatomical and physiological features make the liver particularly suitable for gene-based therapeutic strategies, including its extensive vascularization, fenestrated sinusoidal endothelium, and high metabolic capacity. In the past decade, liver-directed gene therapies have evolved from experimental concepts to clinical applications for various inherited and systemic disorders. Adeno-associated viral vectors, lentiviral systems, and lipid nanoparticles are currently the main platforms for delivering therapeutic genes and genome-editing tools to hepatocytes. Genome editing technologies such as CRISPR-Cas nucleases, base editors, and prime editors have enabled more precise modification of endogenous loci. Early clinical studies in disorders like hemophilia, transthyretin amyloidosis, ornithine transcarbamylase deficiency, and Crigler-Najjar syndrome show that partial correction of hepatic gene function can lead to meaningful clinical benefits. However, several challenges hinder broader clinical implementation, including immune responses to viral capsids and nanoparticle components, dose-dependent toxicity, limited packaging capacity of some vectors, and uncertainties about long-term safety and durability, especially in pediatric populations. Efficient and cell-type-specific delivery beyond hepatocytes remains a major challenge, particularly for diseases driven by non-parenchymal cells or malignant transformation. This article discusses recent advancements in delivery technologies and genome editing approaches for liver disease, as well as current translational barriers and emerging strategies aimed at enhancing specificity, durability, and safety. Collectively, these advances suggest that increasingly precise and programmable gene-based interventions may play a central role in future therapies for a broad spectrum of liver diseases.

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2026-05-25 | Unilateral cerebral injury mimicking hemiconvulsion-hemiplegia-epilepsy syndrome in a boy with newly diagnosed infantile-onset ornithine transcarbamylase deficiency: A case report and literature review

Background Ornithine transcarbamylase deficiency, the most common urea cycle disorder, typically presents with neurological symptoms caused by hyperammonemia. Although brain injuries are typically diffuse, unilateral lesions have been reported. Hemiconvulsion–hemiplegia–epilepsy syndrome is a neurological disorder occurring in infancy or early childhood, characterized by prolonged unilateral seizures, subsequent cerebral hemiatrophy, and epilepsy. These conditions may have overlapping clinical features. Case A 4-month-old boy presented with fever and asymmetric seizures during an adenovirus infection. Blood tests revealed hyperammonemia, elevated liver enzyme levels, coagulopathy, and lactic acidosis. Brain MRI showed diffuse cortical edema in the left hemisphere with abnormal EEG discharges. Hemiconvulsion–hemiplegia–epilepsy syndrome was provisionally suspected, and steroid pulse therapy and supportive treatment were initiated. Due to fluctuating blood ammonia levels, arginine was administered. Further metabolic evaluation demonstrated increased urinary orotic acid excretion, low plasma citrulline and arginine levels, and elevated plasma glutamine. A family history of neonatal-onset disease supported the clinical diagnosis. The patient was treated with a protein-restricted diet, citrulline, arginine, and sodium phenylbutyrate. At 1 year and 2 months of age, he showed mild right upper limb weakness without epilepsy. A review of the literature identified seven cases of urea cycle disorders with unilateral brain lesions, six involving ornithine transcarbamylase deficiency. Conclusion In ornithine transcarbamylase deficiency, acute infection may trigger unilateral cerebral injury, mimicking the hemiconvulsion–hemiplegia–epilepsy syndrome. Early metabolic intervention may help mitigate hyperammonemia and reduce the risk of neurological injury, highlighting the importance of considering metabolic disorders in infants with unilateral brain injury.

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2026-04-23 | Profiling and Targeting of Regulatory RNAs to Upregulate Gene Expression

Abstract Transcription of long noncoding RNAs (lncRNAs), including enhancer RNAs (eRNAs) and promoter-associated RNAs (paRNAs), collectively termed regulatory RNAs (regRNAs), is a hallmark of active gene expression, yet it remains unknown whether regRNAs can be targeted to selectively enhance transcription in cis . We developed regRNA Capture-seq, a high-throughput method to profile regRNAs, and applied it to primary human hepatocytes, annotating thousands of regRNAs at ∼2,000 enhancers and promoters. Using this approach, we interrogated a genetically validated enhancer of the ornithine transcarbamylase ( OTC ) gene, mutations of which cause OTC deficiency (OTCD), the most common urea cycle disorder. Antisense oligonucleotides (ASOs) targeting enhancer-derived regRNAs led to dose-dependent upregulation of OTC in hepatocytes. Mechanistically, ASOs altered regRNA structure, elevated regRNA levels, displaced transcriptional repressors, and increased H3K27 acetylation at the targeted enhancer. This work establishes a potential therapeutic strategy for addressing haploinsufficiency and highlights regRNAs as actionable targets for ASO-mediated upregulation of gene expression.

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