Hepatoblastoma (HB) is the most common malignant liver tumor in children under five years of age. Although globally rare, it accounts for a large proportion of liver cancer in children and has poor survival rates in high-risk and metastatic cases. This review discusses the molecular mechanisms, diagnostic methods, and therapeutic strategies of HB. Mutations in the CTNNB1 gene and the activation of the Wnt/β-catenin pathway are essential genetic factors. Furthermore, genetic syndromes like Beckwith–Wiedemann syndrome (BWS) and Familial Adenomatous Polyposis (FAP) considerably heighten the risk of associated conditions. Additionally, epigenetic mechanisms, such as DNA methylation and the influence of non-coding RNAs (ncRNAs), are pivotal drivers of tumor development. Diagnostics include serum biomarkers, immunohistochemistry (IHC), and imaging techniques. Standard treatments are chemotherapy, surgical resection, and liver transplantation (LT). Emerging therapies like immunotherapy and targeted treatments offer hope against chemotherapy resistance. Future research will prioritize personalized medicine, novel biomarkers, and molecular-targeted therapies to improve survival outcomes.

Cuproptosis, an emerging form of programmed cell death, is capable of inducing mitochondrial dysfunction. Moreover, the PI3K‐AKT‐mTOR signaling pathway contributes to tumor cell progression by reprogramming mitochondrial morphology and function. In this study, we have designed copper complex nanoparticles (NP ^Cu ) and PI3K‐AKT‐mTOR inhibitor Alpelisib nanoparticles (NP ^ALP ) that enhance the efficacy of cuproptosis‐based therapies. NP ^Cu triggers mitochondrial dysfunction and promotes the aggregation of lipoylated dihydrolipoamide S‐acetyltransferase (DLAT), while NP ^ALP inhibits the PI3K‐AKT‐mTOR signaling pathway to induce apoptosis. The combination of these two nanoparticles (NP ^Cu +NP ^ALP ) effectively activates the antitumor responses in the tumor microenvironment (TME). When combined with an anti‐programmed cell death protein 1 antibody (α‐PD‐1), NP ^Cu +NP ^ALP significantly inhibits tumor progression and activates antitumor immunity, offering a promising strategy for liver cancer treatment.