Potential of lncRNAs to regulate cuproptosis in hepatocellular carcinoma: Establishment and validation of a novel risk model

Cuproptosis, a distinct form of programmed cell death, is an emerging field in oncology with promising implications. This novel mode of cell death has the potential to become a regulatory target for tumor therapy, thus expanding the currently limited treatment options available for patients with cancer. Our research team focused on investigating the role of functional long noncoding RNA (lncRNAs) in hepatocellular carcinoma (HCC). We were particularly intrigued by the potential implications of HCC-lncRNAs on cuproptosis. Through a comprehensive analysis, we identified three cuproptosis-related lncRNAs (CRLs): AC018690.1, AL050341.2, and LINC02038. These lncRNAs were found to influence the sensitivity of HCC to cuproptosis. Based on our results, we constructed a risk model represented by the equation: risk score = 0.82 * AC018690.1 + 0.65 * AL050341.2 + 0.61 * LINC02038. Notably, significant disparities were observed in clinical features, such as the response rate to immunotherapy and targeted therapy, as well as in cellular characteristics, including the composition of the tumor immune microenvironment (TIME), when comparing the high- and low-risk groups. Most importantly, knockdown of these CRLs was confirmed to significantly weaken the resistance to cuproptosis in HCC. This effect resulted from the accelerated accumulation of lipoacylated-DLAT and lipoacylated-DLST. In summary, we identified three CRLs in HCC and established a novel risk model with potential clinical applications. Additionally, we proposed a potential therapeutic method consisting of sorafenib-copper ionophores-immunotherapy.