Integrating ferroptosis and the tumor-immune gene mutations interface: a novel lenvatinib resistance prognostic signature with YWHAB-related immunotherapeutic correlates in hepatocellular carcinoma

Background Lenvatinib resistance represents a major clinical challenge in the treatment of hepatocellular carcinoma (HCC), necessitating the identification of strategies to overcome this issue. Although ferroptosis, a non-apoptotic cell death process, is implicated in the progression of HCC and the response to lenvatinib, the prognostic relevance and the lenvatinib response-related mechanisms of ferroptosis-related genes (FRGs) remain poorly understood. Methods An eight-gene ferroptotic lenvatinib-related prognostic signature (FLRPS) was developed as a prognostic model. Based on the median risk score, the patients were classified into high-risk and low-risk groups to compare clinical outcomes, immune traits, and mutational profiles. Immunohistochemistry, spatial transcriptome analysis and single-cell RNA sequencing (scRNA-seq) were used to identify the specificity of YWHAB expression in HCC. In vitro and in vivo assays were utilized to evaluate the impact of YWHAB on the phenotypes of HCC cells and lenvatinib-induced ferroptosis, as well as to investigate the underlying mechanisms. Results The FLRPS, comprising eight genes (CENPA, RAN, CDCA8, KIF2C, YWHAB, HDAC2, DYNC1H1, and NRAS), yielded scores that positively correlated with poorer prognosis, advanced pathological grade, later clinical stage, metrics of genomic instability, and lower M2 macrophage infiltration. Furthermore, a nomogram integrating the FLRPS and tumor stage accurately predicted overall survival. Additionally, lenvatinib-resistant HCC samples exhibited elevated YWHAB expression. Downregulation of YWHAB sensitized Hepa1–6 cells to lenvatinib both in vitro and in vivo , an effect accompanied by decreased GPX4 levels and reversed by liproxstatin-1, suggesting a ferroptosis-related mechanism involving PI3K/AKT pathway inhibition. Conclusions The FLRPS serves as an effective predictive model for the prognosis of HCC. Targeting YWHAB may represent a promising therapeutic strategy to overcome lenvatinib resistance in HCC.