Metal Ion Transporter SLC39A14-Mediated Ferroptosis and Glycosylation Modulate the Tumor Immune Microenvironment: A Pan-Cancer Multi-Omics Exploration of Therapeutic Potential

Read the full article See related articles

Listed in

This article is not in any list yet, why not save it to one of your lists.
Log in to save this article

Abstract

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a pivotal mechanism in cancer progression and therapeutic resistance. Concurrently, glycosylation, a key post-translational modification, plays a critical role in regulating cell signaling, immune evasion, and metastasis. Although both processes are individually implicated in tumor biology, the intersection between ferroptosis and glycosylation remains largely unexplored. We performed a comprehensive pan-cancer analysis by integrating transcriptomic, epigenomic, single-cell RNA sequencing, and pharmacogenomic datasets. Ferroptosis- and glycosylation-related genes were curated from the MSigDB, leading to the identification of metal ion transporter SLC39A14 (solute carrier family 39 member 14) as a common intersecting gene. A ferroptosis-related gene signature was constructed using LASSO Cox regression, followed by survival, immune microenvironment, and functional enrichment analyses across The Cancer Genome Atlas (TCGA) cohort. Drug sensitivity analysis and AlphaFold-based molecular docking were used to evaluate therapeutic relevance. SLC39A14 was significantly upregulated in multiple tumor types and strongly associated with poor prognosis, immune-stromal infiltration, and ferroptosis resistance. Notably, among all cancer types analyzed, glioblastoma multiforme (GBM) and kidney renal clear cell carcinoma (KIRC) exhibited the strongest prognostic associations and the most significant differential expression of SLC39A14. These two tumors also showed distinct but clinically relevant ferroptosis-immune phenotypes: GBM featured enrichment of VEGF and NRF2 oxidative stress pathways in a hypoxia-adapted, macrophage- and NK cell–infiltrated microenvironment, while KIRC was characterized by TF-induced thrombosis, DNA damage response, and immune exclusion. Single-cell transcriptomic and DNA methylation analyses further confirmed SLC39A14’s role in modulating tumor microenvironment and ferroptotic vulnerability. Functional enrichment revealed that high ferroptosis scores were enriched in angiogenesis, EMT, and cytokine signaling pathways. A nomogram integrating SLC39A14 with clinical parameters showed enhanced survival prediction. Moreover, SLC39A14 expression correlated with differential responses to ferroptosis-related drugs, suggesting translational applicability. This study highlights the dual regulatory role of SLC39A14 at the interface of ferroptosis and glycosylation, with a distinct impact on GBM and renal cancer progression. By integrating multi-omics and single-cell analyses, we reveal SLC39A14 as a promising prognostic biomarker and therapeutic target, particularly in brain and kidney cancers where ferroptosis modulation may offer novel clinical opportunities.

Article activity feed