PANoptosis，是细胞中凋亡、火焰病毒感染、和坏死的一种相互作用，深度参与了癌症的发展和免疫。然而，PANoptosis在肝细胞癌（HCC）中的影响还需要进一步研究。在肿瘤基因组图谱（TCGA）数据库中筛选了差异表达的PANoptosis相关基因（PANRGs）。接着进行突变检测、生物信息学和一致性聚类分析。然后，通过最小绝对收缩和选择算子（LASSO）Cox回归建立了预后风险模型。此外，还探索了风险模型的预后价值、免疫相关性和治疗反应预测能力。在TCGA-HCC队列中总共有18个不同表达的PANRGs，主要涉及癌症和细胞死亡相关的信号通路。使用无监督聚类方法，我们识别出了两个由PANRGs介导的聚类模式。两个聚类之间在总生存率（OS）和临床特征上的显著差异分别加以证明。基于五个基因预后风险模型，计算的PANRG-分数被用来将亚组分为高风险和低风险。值得注意的是，高风险亚组预后较差，免疫浸润水平明显低于低风险亚组的肥大细胞、自然杀伤细胞和pDCs，但高于aDCs、iDCs和Treg细胞的水平。此外，我们构建了一个可靠的预后图表，结合临床特征和PANRG-分数，用于预测肝细胞癌患者的OS。揭示了PANoptosis与肿瘤突变负荷（TMB）和铁死亡之间的显著负相关。在药物敏感性分析中，高风险亚组的TIDE分数明显降低，表明对免疫治疗的反应更好，并且可能对Tipifarnib、Imatinib、Doxorubicin和Gemcitabine更敏感。通过对广西队列中的16对HCC组织验证了FADD的上调mRNA表达。基于PANoptosis相关基因构建了一个综合风险签名，为患者分层和预测肝细胞癌患者的预后提供了路线图。PANRG-分数较高的患者可能具有不良的存活率和相对较低的免疫浸润，但对免疫治疗的潜在反应更好。因此，未来的HCC治疗方案应注重PANoptosis的设定，以实现个体化、可行和有效的治疗方案。© 2023. Springer Nature Limited.

PANoptosis, an interplay between pyroptosis, apoptosis, and necroptosis, is deeply involved in cancer development and immunity. However, the influence of PANoptosis in hepatocellular carcinoma (HCC) remains to be further investigated. The differentially expressed PANoptosis-related genes (PANRGs) was screened in The Cancer Genome Atlas (TCGA) database. Accordingly, mutation, bioinformatics, and consensus clustering analyses were performed. Then, a prognostic risk model was developed by least absolute shrinkage and selection operator (LASSO) Cox regression. Furthermore, the prognostic value, immunity correlation and therapeutic response prediction ability of risk model were explored. A total of 18 PANRGs were differently expressed in the TCGA-HCC cohort and were mainly involved in cancer- and cell death-related signal pathways. Using unsupervised clustering method, we identified two PANRGs-mediated clustering patterns. The remarkable differences between the two clusters on overall survival (OS) and clinical features were demonstrated respectively. Based on the five-gene prognostic risk model, the calculated PANRG-scores were used to categorize the subgroups as high- and low-risk. Notably, the high-risk subgroup had a dismal prognosis and exhibited much lower immune infiltration levels of mast cells, nature killer cells and pDCs, but higher levels of aDCs, iDCs and Treg cells than those in the low-risk subgroup. Furthermore, we constructed a reliable nomogram combining clinical traits and PANRG-score to predict the OS of HCC patients. The significantly negative correlation between PANoptosis and tumor mutation burden (TMB), ferroptosis were revealed. In drug sensitivity analysis, the high-risk subgroup had a considerably lower TIDE score, suggesting a preferable response to immunotherapy, and may be more sensitive to Tipifarnib, Imatinib, Doxorubicin, and Gemcitabine. The upregulated mRNA expressions of FADD were validated in 16 paired HCC tissues of Guangxi cohort. Based on PANoptosis-related genes, an integrated risk signature was constructed to provide a roadmap for patient stratification and predict HCC patient's prognosis. The patients with the higher PANRG-score may carry a dismal survival and relatively low immune infiltration, but a potential better immunotherapy response. Therefore, future HCC therapy perspectives should emphasize the setting of PANoptosis to achieve a personalized, practicable and effective therapeutic regimen.© 2023. Springer Nature Limited.