Multi-cohort screening of PANoptosis-related genes reveals PARP1 as a key target, and AZD5305 exerts anti-tumor effects in neuroblastoma.
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BACKGROUND: Neuroblastoma (NB) is the most prevalent extracranial solid malignant tumor in infants and children. Approximately half of children with high-risk NB exhibit primary resistance to first-line therapy or experience disease relapse within two years post-treatment, leading to dismal overall survival. PANoptosis is an inflammatory programmed cell death modality integrating pyroptosis, apoptosis and necroptosis; nevertheless, the functional relevance of PANoptosis-related genes (PRGs) in NB remains largely undefined. This study aimed to explore PRGs associated with NB prognosis and their link to the tumor immune microenvironment, so as to identify novel therapeutic targets for NB. METHODS: mRNA expression profiles from three public NB datasets (GSE49711-NB, TARGET-NB and E-MTAB-8248-NB) were used to investigate the prognostic roles of 19 previously reported PRGs. Independent Cox regression screening was performed in each cohort to identify cohort-specific prognostic PRGs, followed by Venn intersection analysis to identify conserved prognostic genes. PARP1 expression was validated in tumor tissues from 127 clinical NB patients. The GIS score based on PARP1 expression and clinical metadata were combined to assess its prognostic value. In vitro functional assays were performed to explore the anti-tumor effects and mechanisms of the PARP1 inhibitor AZD5305. RESULTS: Venn intersection analysis identified PARP1 as the only shared gene with consistent prognostic significance across heterogeneous NB patient populations. In vitro experiments revealed that AZD5305 markedly suppressed NB cell proliferation, migration and invasion, triggered cell apoptosis, and arrested cell cycle progression at the G0/G1 phase. CONCLUSION: This study adopts a multi-cohort parallel screening strategy to mine conserved therapeutic targets for NB. Our data indicate that PARP1 inhibition via AZD5305 represents a promising therapeutic strategy for NB treatment.