Patients with germline neurofibromatosis type 1 (NF1) microdeletions frequently exhibit hereditary syndromes such as cardiovascular anomalies and have an increased risk of malignant peripheral nerve sheath tumors (MPNSTs). This study aimed to identify the genes codeleted with SUZ12 that are related to MPNST. We used differential gene expression and enrichment analyses to analyze the SUZ12-mutant and SUZ12-wild-type gene expression profiles in the GSE118186 and GSE66743 datasets in Gene Expression Omnibus (GEO). PPI network analysis combined with MPNST patient survival analysis was used to identify ADCY1, which catalyzes the conversion of ATP to cAMP, as a key gene. Moreover, chromatin immunoprecipitation sequencing (ChIP-Seq) showed that the distribution of H3K27me3 in the ADCY1 promoter region and gene body was significantly reduced in SUZ12-mutant cells. To verify the role of ADCY1 in SUZ12 mutation, we used RNA interference and plasmid transfection to interfere with SUZ12 expression in plexiform neurofibroma (pNF) and MPNST cell lines and then treated the cells with forskolin, IBMX and H89. ERK phosphorylation was accelerated and prolonged after siRNA transfection, especially in ipNF05.5 cells, and the intensity and duration of ERK activation were reduced after SUZ12 overexpression. Importantly, the level of p-ERK was consistent with that of Rap1-GTP. Moreover, H89 completely blocked Rap1 activation and the changes in the p-ERK level after SUZ12 siRNA transfection. In conclusion, our findings suggested that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras signaling through the ADCY1/cAMP/Rap1/ERK pathway and that SUZ12 may serve as a therapeutic and prognostic biomarker in NF1-associated neurofibromas.

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell-derived sarcomas that are sporadic or associated with Neurofibromatosis 1 (NF1) gene mutations. Traditional therapies are usually ineffective for treating MPNSTs, so new targets need to be identified for the treatment of MPNSTs. In the present study, the role of the mitochondrial translocator protein (TSPO) in the regulation of cell proliferation and the cell cycle in MPNSTs was investigated. TSPO expression was lower in MPNSTs than in NFs. Loss-of-function experiments revealed that TSPO deficiency promoted MPNST cell growth, migration, and invasion and influenced the cell cycle in vitro and in vivo. In addition, TSPO depletion suppressed cell apoptosis by downregulating the expression of caspase-3, caspase-8, HSP60, p27, p53, and BCL-2 and suppressed the cell cycle by upregulating CDK1, CDK2, CCNB1 and CCNA2. Furthermore, CDK1 was determined to be an upstream target of TSPO-mediated regulation via RNA-seq, qPCR, and Western blotting. Specifically, depletion of CDK1 weakened the effect of TSPO deficiency on cell proliferation and migration. More importantly, CDK1 knockdown induced significant cell cycle arrest in the G2/M phase. In summary, TSPO deficiency regulates the cell cycle in MPNSTs by targeting CDK1, which may be an effective molecular target for prognosis evaluation and treatment.

Intracranial infections are challenging to diagnose, especially in immunocompromised patients. Next-generation sequencing (NGS) has emerged as a powerful tool for broad pathogen detection, including Torque Teno Virus (TTV). Elevated TTV loads have been associated with immune dysfunction, potentially serving as a biomarker for opportunistic infections. However, the clinical significance of TTV in intracranial infections remains unclear. An 8-year-old boy developed a complex intracranial infection following craniotomy, characterized by elevated TTV levels in cerebrospinal fluid (CSF) and subsequent fungal co-infection. Initial empirical antibiotics failed to fully control the infection. NGS identified TTV in the CSF, prompting the addition of intravenous immunoglobulin. Recurrent infection led to the suspicion of a fungal infection, confirmed by positive G/GM tests and successful treatment with fluconazole. Elevated TTV levels in CSF may indicate underlying immunodeficiency and predispose patients to opportunistic fungal infections. Prompt fungal testing including qPCR is recommended when TTV is detected in CSF. Further research is needed to elucidate the role of TTV in clinical infections and optimize management strategies.

Background: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma characterized by high recurrence and poor prognosis, necessitating the search for novel therapeutic targets and strategies. This study investigated the expression of mitochondrial translocator protein (TSPO) in MPNST and its role in regulating ferroptosis.Methods: TSPO expression was analyzed in adjacent non-tumor tissues, benign neurofibromas, and malignant tissues using real-time PCR, western blotting, immunohistochemistry staining. Expression levels of classic ferroptosis markers, including AKR1C1 and FTH1 were assessed. Ferroptosis was evaluated by measuring cell viability, ferroptosis marker levels, and intracellular Fe²⁺ and reactive oxygen species (ROS) levels. Oxidized phospholipid profiles of wild-types and TSPO knockdown MPNST cells were determined using liquid chromatography-mass spectrometry. The potential role of GPX4 in mediating TSPO’s effect on ferroptosis was investigated in vitro.Results: Compared with adjacent non-tumor tissues and benign neurofibromas, TSPO expression was significantly lower in MPNST specimens. Notably, TSPO expression positively correlated with the classic ferroptosis markers AKR1C1 and FTH1. TSPO-knockdown MPNST cells exhibited significant resistance to ferroptotic cell death. Additionally, biochemical characterization indicated that TSPO deficiency decreased intracellular Fe²⁺ and ROS. Furthermore, oxidized phospholipids were remarkably reduced in TSPO-knockdown cells. TSPO enriches cellular oxidized phospholipids by downregulating GPX4-GSH antioxidant pathway. Furthermore, GPX4 is elevated in malignant tumors compared to benign specimens and negatively correlated with TSPO expression in clinical tumor specimens.Conclusion: Our findings revealed that TSPO deficiency inhibited ferroptosis in MPNST cells by upregulating GPX4 antioxidant pathway, suggesting that mitochondrial TSPO-GPX4-ferroptosis axis may be a promising therapeutic target for improving the outcomes of patients with MPNST.