The role of lactate metabolism in retinoblastoma tumorigenesis and ferroptosis resistance

The Warburg effect, a hallmark of cancer, describes the preference of cancer cells for glucose metabolism via aerobic glycolysis, leading to substantial lactate accumulation. However, the role of lactate metabolism in retinoblastoma, the primary intraocular malignancy in children, remains unclear. This study aimed to elucidate the gene expression profiles associated with lactate metabolism in retinoblastoma and their impact on tumorigenesis and ferroptosis resistance. The involvement of metabolic characteristics in retinoblastoma was analyzed by comparing single-cell RNA sequencing transcriptome profiles from normal retina tissues and retinoblastoma tissues from patient samples. The effects of lactate on retinoblastoma cell line viability and its mechanisms were examined both in vitro and in vivo. Single-cell RNA sequencing analysis revealed enhanced glycolysis in retinoblastoma cells and significant differences in lactate metabolism-related gene expression among various retinoblastoma cell types. Retinoblastoma cell lines with moderate lactate levels exhibited increased viability and resistance to ferroptosis induced by ferroptosis inducers. Additionally, lactate promoted the upregulation of monocarboxylate transporter 1 (MCT1), which facilitated lactate transport, in a dose-dependent manner in retinoblastoma cell lines. Knocking down MCT1 reduced both viability and ferroptosis resistance of retinoblastoma cell lines in a lactate-rich environment. In vivo, disrupting lactate transport through MCT1 inhibition suppressed retinoblastoma tumorigenesis and invasion in a mouse xenograft model, and this effect was reversed by the ferroptosis inhibitor liproxstatin-1. These findings highlighted the crucial role of lactate metabolism in retinoblastoma tumorigenesis and resistance to ferroptosis.