Liver cancer is one of the major cancer types and among the most malignant liver diseases around the world (1–5). Liver cancer comprises several sub-types, including hepatocellular carcinoma (the most common type of liver cancer), cholangiocarcinoma, hepatoblastoma, and angiosarcoma (1). Liver cancer causes great healthy and economic burdens to the people and the society of both developed and underdeveloped area. According to the estimation of epidemiologists, there were about 905,677 new cases of liver cancer and 830,180 new deaths caused by it (2). In the US, although liver cancer is not among the top 10 cancer types regarding the estimated new cases in 2022, it may cause more than 30,000 deaths in the same year, which ranks 5^th in all the cancer types (6). Albeit the dramatic development in the diagnosis and treatment of liver cancer in the past decades, its mortality increases rapidly, partially due to the change of environment, life style, and dietary habit (1, 7, 8). For scientific and clinical researchers, elucidating the underlying mechanism for the initiation and development of liver cancer is a crucial and long-term task. In the meantime, development of novel prognostic biomarker for liver cancer patients will greatly benefit their treatments (1, 9).

For the somatic cells in mammalian life, the equilibrium between cell death and proliferation is of vital importance. To achieve a concerted life circle, human cells “master” multiple regulated cell death (RCD) modalities (including apoptosis, ferroptosis, necroptosis, and pyroptosis) evolutionally (10). During normal development, these RCDs cooperate with each other to orchestrate a suitable rate of cell turnover in different organs. In addition, these RCDs also function in dealing with various inner or environmental stresses. From a clinical perspective, these RCDs have been demonstrated to be involved with a wide range of disease processes, including organ injury, immune system dysfunction, neurodegenerative disorder, and particularly tumor (10). Identifying novel RCD type will not only deepen our understanding of the human cell, but also create new therapeutic opportunity for lots of diseases, including liver cancer. Cuproptosis is a quite recently discovered RCD mode, which is characterized by unique features different from other RCDs mentioned above (11). Cuproptosis is caused by copper-induced aggregation of lipoylated proteins in TCA cycle. The data in the seminal paper suggested that cuproptosis may participate in the modulation of various diseases, including cancer. Whether cuproptosis is associated with liver cancer has not been investigated. However, it is of evident significance to explore the potential link between liver cancer and cuproptosis (and essential genes underlying it).

Long non-coding RNA (lncRNA) is one of the research hotspots in these years (12). This is a family of RNAs with diverse lengths, localizations, structures, and functions. The dysregulation of lncRNAs have been demonstrated to be involved in the progression of various tumor types, including liver cancer (13). These lncRNAs can not only be therapeutic targets in liver cancer treatment, but may also constitute unique expression profiles to indicate distinct characteristics of liver cancer, including the malignant stage, the sensitivity to therapeutics, and the prognosis of patients (14). Particularly, differential lncRNA expression profiles can be established based on specific cellular processes. Constructing a solid lncRNA signature in the context of a crucial activity in liver cancer cell will be of great use for predicting the development of liver cancer in patients.

In this study, we leveraged our current knowledge about liver cancer, cuproptosis, and lncRNA to construct a novel prognostic model based on cuproptosis-related lncRNAs and mRNAs in liver cancer. This model fits well with diverse pathologic parameters of liver cancer. Moreover, this model has been successfully validated by using a batch of patients’ data. We believe that, this model can be beneficial to the prognosis of liver cancer patients.

Copper is an essential mineral for human health (24). The fact that dysregulation of copper level will cause damage to the normal cell life has been known for a long time. The discovery of cuproptosis makes an interesting and important explanation for this phenomenon (25). Although the field of cuproptosis is just in its infancy, it is reasonable to speculate that this cell death mode has tight correlation with human diseases, including liver cancer. There are two basic elements for the initiation of cuproptosis: copper and lipoylated protein. About the first element, liver is the central organ for the metabolism of copper (26, 27). For the lipoylated proteins, most of them function in the TCA cycle in the mitochondrion. To avoid cuproptosis, these two elements must be maintained in check. In liver cancer cell, dysregulation of the normal gene regulatory network is a major hallmark, which applies to the essential genes associated with copper metabolism and TCA cycle (28, 29). It will not be surprising that liver cancer cell may be one of the major sites where cuproptosis happens. We believe that in the near future, the regulation and the pathologic relevance of cuproptosis will be revealed in liver cancer. Before that, if we can utilize the key genes in cuproptosis to make a prognostic model for liver cancer patient, this will accelerate the translation of this field to clinical practice, which also applies to other tumor types (30).

Given the severe threat of liver cancer to human society, much more efforts are needed to figure out the etiology and pathogenesis of liver cancer and develop effective therapeutics to treat it. In the meantime, advances in the diagnosis and prognosis techniques for liver cancer are of urgent demand. In this study, we leveraged the lncRNA and mRNA associated with cuproptosis to make a novel prognostic signature for liver cancer. In this model, we incorporated 6 lncRNAs (POLH-AS1, AL117336.2, MKLN1-AS, AC005479.2, AL928654.1, and AL031985.3) and 3 mRNAs (ATP7A, DLAT, and GLS) after a stringent selection process ( Figures 1 , 2 ). Our model exhibits an effective application in the prognosis of liver cancer patient ( Figures 3 , 4 ). Our model is capable of reflecting several major hallmarks (including the immune cell infiltration and TMB) of liver cancer ( Figures 5 , 6 ). This model also satisfactorily passed the validation procedure. The inclusion of the 3 mRNAs is an advantage of our model compared with those only analyze lncRNA. These proteins encoded by the 3 mRNAs are closely related to the induction of cuproptosis. ATP7A is a copper exporter, which is essential for the homeostasis of intracellular copper level (31). Mutation of ATP7A is demonstrated to be associated with Menkes disease, occipital horn syndrome, and X-linked distal spinal muscular atrophy (32). It will be interesting to investigate whether there is liver cancer-related mutation in ATP7A gene and if so, whether this mutation will affect cuproptosis and liver cancer development. DLAT is an important subunit of the PDH complex and also one of the major substrates for cuproptosis (33). A recent study found that the DLAT level in hepatocellular carcinoma was influenced by blueberry malvidin-3-galactoside and 5-fluorouracil (34). This may establish links between cuproptosis and intestinal microbiota and chemotherapy of liver cancer. GLS, as a mitochondrial glutaminase, which hydrolyzes glutamine to glutamate, has a close relationship with liver cancer progression (35, 36). Huang et al. revealed that GLS along with PDH complex was important in liver cancer metabolism and autophagy, which might be the underlying mechanism for the chemo-resistance of liver cancer cell (37). Whether cuproptosis participates in the regulation of sensitivity to chemotherapy of liver cancer cell needs to be clarified in the future. For these lncRNAs, several of them have been linked with other RCDs like ferroptosis (POLH-AS1, MKLN1-AS, AL928654.1, and AL031985.3) and pyroptosis (MKLN1-AS, AC005479.2, and AL031985.3) in liver cancer (38–41). Their involvement with cuproptosis suggests there may be molecular relevance between those distinct RCDs. In fact, these RCDs do share similar mechanism of initiation (for example, ROS triggers apoptosis and ferroptosis), regulator (like Caspases in apoptosis, pyroptosis, and necroptosis; metal ion in ferroptosis and cuproptosis), and function (for example, apoptosis, ferroptosis, and pyroptosis all modulate immune activity) (10, 11). We wish future researches will shed more light on the link between these different RCDs. Moreover, POLH-AS1, AC005479.2 and AL928654.1 have been found to involve immune response in papillary thyroid cancer and hepatocellular carcinoma, respectively (42–44). Our model not only incorporates these two lncRNAs, but also expand this list of immune-associated lncRNAs in liver cancer to other 4 lncRNAs. AL117336.2 is a novel lncRNA with little study to date. It is worthy to explore its potential role in liver cancer and cuproptosis in the future. As hypoxia can dramatically influence TCA cycle and mitochondrion function, our results may reveal a link between hypoxia and cuproptosis in liver cancer ( Figure 5D ) (21). Another interesting result about our model is its correlation with TMB in liver cancer, which is related to the sensitivity of liver cancer cell to several chemotherapeutic drugs ( Figure 6 ). A notable point is the mutual exclusiveness or co-occurence of p53 mutation and mutations of other genes. p53 here is of vital pathological relevance, not only because it is among the most important tumor suppressor genes, but also that it is a master regulator of several RCDs, including apoptosis, ferroptosis, and pyroptosis (45–47). p53 also has vital role in regulating TCA cycle (45). It should be one major direction to study whether p53 can regulate cuproptosis or not in liver cancer.

To sum up, we established an effective prognostic signature in liver cancer based on cuproptosis-related lncRNAs and mRNAs. We believe that this work will not only benefit the liver cancer patient in clinical use, but also make useful suggestions for the research field of cuproptosis. We wish in the near future, there will be great advances in researches about cuproptosis in liver cancer, based on which we can validate and improve our model to make it more accurate and efficient.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author. The public datasets analyzed in this study can be found in the TCGA (https://portal.gdc.cancer.gov/) and GEO (https://www.ncbi.nlm.nih.gov/geo/) repository.

LM and YQL conceived the project. YL, YQL, and HF analyzed the data. YL, YQL, SY, and HF wrote the manuscript. LM reviewed and revised the manuscript. The authors read and approved the final manuscript. The requirements for authorship have been met. Each author believes that the manuscript represents honest work.

This work was supported by grants from the Natural Science Foundation of Jilin Province, China [20210101248JC].

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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