2026-08-13 | Disarming cGAS-STING hyperactivation in autoimmune and inflammatory diseases: Pathogenic mechanisms and emerging therapeutic strategies.
Aberrant activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been increasingly recognized as a key driver of autoimmune and inflammatory diseases. In recent years, accumulating evidence has highlighted the close association between cGAS-STING signaling and the pathogenesis of these disorders, suggesting that pharmacological targeting of this pathway may represent a promising therapeutic strategy. This review provides a comprehensive overview of the molecular mechanisms underlying cGAS-STING hyperactivation and its pathological roles across diverse diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), non-alcoholic steatohepatitis (NASH), STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), COPA syndrome, Niemann-Pick disease type C (NPC), neurodegenerative diseases and cancer. We critically evaluate current and emerging pharmacological strategies targeting the cGAS-STING pathway, encompassing direct cGAS and STING inhibitors, protein degradation technologies, epigenetic modulation, regulation of biomolecular phase separation, and artificial intelligence (AI)-enabled drug discovery approaches. By integrating disease-specific pathogenic mechanisms with therapeutic opportunities, this review highlights key challenges and future directions in the development of cGAS-STING-targeted therapies. Collectively, these insights provide a translational perspective for precision targeting of pathological cGAS-STING activation.
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2026-08-12 | Mito-TEMPO improves survival rates in npc1 -knockout zebrafish by reducing oxidative stress and enhancing mitophagy via Sod2
Niemann-Pick type C (NPC) disease is a lysosomal storage disorder primarily caused by mutations in the NPC1 gene. Most patients present with early-life symptoms including hepatosplenomegaly and digestive system impairment, followed by progressive neurodegeneration. However, effective therapeutic approaches to improve survival in NPC disease remain limited. In this study, using an npc1 -knockout (NPC1-KO) zebrafish model established in our laboratory, our team suggests that npc1 deficiency appears to correlate with marked down-regulation of superoxide dismutase 2 (Sod2) expression, concurrent with excessive oxidative stress (OS), mitochondrial dysfunction, and defective mitophagy. Treatment with Mito-TEMPO, a mitochondria-targeted antioxidant acting on SOD, increased survival rates and ameliorated cholesterol accumulation and liver function impairment in early-stage NPC1-KO zebrafish. The underlying mechanism may involve attenuation of OS and promotion of PINK1/Parkin-dependent mitophagic flux through SOD2 enhancement. Our findings support Mito-TEMPO as a potential therapeutic agent and SOD2 as a possible target for NPC disease.
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2026-08-09 | Long-term real-world safety and effectiveness of arimoclomol in individuals with NPC: Outcomes from the US early access program over a 4-year period.
The United States-based Early Access Program (US EAP) provided access to arimoclomol for individuals with Niemann-Pick disease Type C (NPC) ineligible or unable to enroll in clinical trials, generating 4 years of real-world safety and effectiveness data. Participants were enrolled at 14 US sites. Investigators collected adverse events (AEs) and assessed disease severity using the 5-domain NPC Clinical Severity Scale (5DNPCCSS) at Baseline and follow-up visits as part of routine clinical care. Among 109 participants, 53 (48.6%) were adults (≥18 years) and 71 (65.1%) received miglustat alongside arimoclomol. Mean (SD) arimoclomol exposure was 820 (539) days. Of 248 reported AEs, 17 events in 13 participants (12.8%) were treatment related. 5DNPCCSS scores remained relatively stable throughout the program, with mean (SD) total scores of 11.0 (6.15) at Baseline (n = 100) and 12.0 (7.32) at Year 4 (n = 22). Among participants with Baseline and Year 1 assessments, mean (SD) scores were 11.2 (6.33) at Baseline and 11.1 (6.63) at Year 1 (n = 78). Similar patterns were observed for those with Baseline and Year 2, Year 3, or Year 4 assessments. Rescored 4-domain NPCCSS (R4DNPCCSS) scores (calculated based on 5DNPCCSS data) showed comparable longitudinal trends. The US EAP provides robust real-world evidence data up to 4 years, supporting the tolerability and effectiveness of arimoclomol in a broad NPC population, including adults and those not treated with miglustat. These findings complement and extend clinical trials results, reinforcing the role of arimoclomol, especially in combination with miglustat, as an important therapeutic option in routine clinical practice.
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2026-08-05 | Neuromodulatory effects of N-acetyl-L-leucine in a human induced neuronal cell culture system
N-acetyl-L-leucine (NALL), an acetylated derivative of the amino acid leucine, has been shown to reduce neuronal cell death and neuroinflammation in murine models. Its beneficial effects in patients with the lysosomal storage disease Niemann-Pick Type C have led to recent FDA and EMA approval. However, neuroprotective effects of NALL remain to be further elucidated. In this study, we investigate and characterize the neuroprotective effects of NALL. To this end, we used human induced primary neurons (hiPNs), which were generated from induced pluripotent stem cells derived from reprogrammed renal proximal tubule epithelial cells obtained from either healthy controls (HC) or individuals with relapsing-remitting multiple sclerosis (MS). We demonstrated that NALL exhibits neuroprotective properties in MS- and HC-derived hiPNs subjected to acute damage induced by the microtubule-destabilizing agent nocodazole determined by neurite length. This effect can be blocked by inhibition of transporter-specific NALL uptake. HiPNs from MS donors treated with NALL expressed higher levels of glutamate cysteine ligase (GCL), the ratelimiting enzyme in glutathione synthesis. MS-specific cells are more susceptible to stress induced by the protein kinase inhibitor staurosporine, whereas in HC-specific cells only, NALL is able to modulate this stress induction. In summary, we demonstrate differential responses to induced stress in MS- and HC-specific neurons and the capacity of NALL to modulate neurite outgrowth and stress mechanisms in this cell culture system. NALL may represent an interesting additive treatment for MS or other diseases associated with oxidative stress and neurodegeneration if further substantiated.
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2026-07-29 | NPC1 deficiency engages a lysosome-genome-immune program linked to neurodegeneration and cellular aging signatures.
Lysosomal dysfunction is a prominent feature of neurodegeneration and aging, yet how primary defects in lysosomal trafficking are converted into progressive cellular decline remains poorly understood. Niemann Pick disease type C (NPC), caused by impaired NPC1 dependent cholesterol export, provides a genetically defined model to address this question. Here, we show that NPC1 deficiency activates a lysosome, genome, immune axis linking cholesterol trafficking failure to neurodegeneration and hallmarks of cellular aging. In Npc1 mutant mice, NPC1 loss triggered DNA damage, neuroinflammation, microglial and astrocytic activation, Purkinje neuron degeneration, and motor dysfunction. Consistently, NPC patient-derived fibroblasts exhibited mitochondrial abnormalities and widespread DNA double-strand breaks. Genome-wide DNA break mapping and transcriptomic analyses revealed extensive genomic instability at regulatory regions, including enrichment of DNA breaks at transcription start sites and G quadruplex associated loci, accompanied by widespread transcriptional reprogramming, activation of innate immune pathways, disruption of fibroblast identity, and induction of cellular aging signatures. We further identify Fingolimod, an FDA approved sphingosine - 1 phosphate receptor modulator, as a potent modifier of this disease network. Fingolimod improved lysosomal cholesterol trafficking, increased LAMP1 abundance, attenuated STING associated inflammatory signaling, normalized mitochondrial function, reduced neuroinflammatory and neurodegenerative phenotypes in Npc1 mutant mice, and broadly shifted disease-associated transcriptional programs toward a healthier state. Extending these findings beyond NPC, Fingolimod improved age-associated phenotypes in C. elegans and prolonged lifespan in aged male mice. Together, these findings identify genome instability and chronic innate immune activation as major downstream consequences of lysosomal cholesterol trafficking failure and establish Fingolimod as a clinically actionable modulator of lysosomal dysfunction, neurodegeneration, and aging-related decline.
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