Squalene epoxidase (SQLE) is a key enzyme in the mevalonate–cholesterol pathway that plays a critical role in cellular physiological processes. It converts squalene to 2,3-epoxysqualene and catalyzes the first oxygenation step in the pathway. Recently, intensive efforts have been made to extend the current knowledge of SQLE in cancers through functional and mechanistic studies. However, the underlying mechanisms and the role of SQLE in cancers have not been fully elucidated yet. In this review, we retrospected current knowledge of SQLE as a rate-limiting enzyme in the mevalonate–cholesterol pathway, while shedding light on its potential as a diagnostic and prognostic marker, and revealed its therapeutic values in cancers. We showed that SQLE is regulated at different levels and is involved in the crosstalk with iron-dependent cell death. Particularly, we systemically reviewed the research findings on the role of SQLE in different cancers. Finally, we discussed the therapeutic implications of SQLE inhibitors and summarized their potential clinical values. Overall, this review discussed the multifaceted mechanisms that involve SQLE to present a vivid panorama of SQLE in cancers.

Background: Lung adenocarcinoma is the most common NSCLC and is associated with metabolic dysregulation. Purine biosynthesis, regulated by PAICS, plays a key role in tumor progression and therapy resistance. Methods: We focused on LUAD using pan-cancer and KEGG enrichment analyses. TCGA-LUAD and three GEO datasets were analyzed to confirm the prognostic relevance of purine biosynthesis. A prognostic model, the Purine Biosynthesis-Related Score (PBRS), was developed using LASSO regression and validated in independent cohorts. Gene set variation analysis, immune profiling, tumor mutational burden analysis, and drug sensitivity analysis were conducted. PAICS expression was validated in LUAD tissues, and its role was assessed via proliferation and migration assays. Results: PBRS classified LUAD patients into high-risk (PBRS-high) and low-risk (PBRS-low) subgroups, with distinct prognostic outcomes. PBRS-high patients showed enrichment in cell cycle regulation and DNA repair pathways and had higher TMB, suggesting potential sensitivity to immunotherapy, although immune escape mechanisms may limit the efficacy of immune checkpoint inhibitors. PBRS-low patients were more responsive to metabolic inhibitors. PAICS overexpression correlated with poor prognosis, while its knockdown suppressed LUAD progression. Conclusion: PBRS is a prognostic tool in LUAD, identifying PBRS-high patients who may benefit from immunotherapy or DDR-targeted therapies. PBRS-low patients exhibit sensitivity to metabolic inhibitors. PAICS is a potential therapeutic target.

Sarcomas are heterogeneous connective tissue malignancies that have been historically categorized into soft tissue and bone cancers. Although multimodal therapies are implemented, many sarcoma subtypes are still difficult to treat. Lipids play vital roles in cellular activities; however, ectopic levels of lipid metabolites have an impact on tumor recurrence, metastasis, and drug resistance. Thus, precision therapies targeting lipid metabolism in sarcoma need to be explored. In this study, we performed a comprehensive analysis of molecular stratification based on lipid metabolism-associated genes (LMAGs) using both public datasets and the data of patients in our cohort and constructed a novel prognostic model consisting of squalene epoxidase (SQLE) and tumor necrosis factor (TNF). We first integrated information on gene expression profile and survival outcomes to divide TCGA sarcoma patients into high- and low-risk subgroups and further revealed the prognosis value of the metabolic signature and immune infiltration of patients in both groups, thus proposing various therapeutic recommendations for sarcoma. We observed that the low-risk sarcoma patients in the TCGA-SARC cohort were characterized by high proportions of immune cells and increased expression of immune checkpoint genes. Subsequently, this lipid metabolic signature was validated in four external independent sarcoma datasets including the CHCAMS cohort. Notably, SQLE, a rate-limiting enzyme in cholesterol biosynthesis, was identified as a potential therapeutic target for sarcoma. Knockdown of SQLE substantially inhibited cell proliferation and colony formation while promoting the apoptosis of sarcoma cells. Terbinafine, an inhibitor of SQLE, displayed similar tumor suppression capacity in vitro. The prognostic predictive model and the potential drug target SQLE might serve as valuable hints for further in-depth biological, diagnostic, and therapeutic exploration of sarcoma.