Hypoxia-induced LGALS8-AS1 sustains oxidative phosphorylation to drive breast cancer progression.

Hypoxia is a defining feature of the breast cancer microenvironment and drives metabolic adaptation during tumor progression. However, the involvement of hypoxia-responsive long noncoding RNAs (lncRNAs) in mitochondrial metabolism remains poorly understood. Here, we identify LGALS8-AS1 as a hypoxia-inducible lncRNA that promotes breast cancer progression by sustaining oxidative phosphorylation (OXPHOS). Transcriptomic profiling of hypoxia-treated T47D and MCF7 cells revealed LGALS8-AS1 as a consistently upregulated lncRNA. LGALS8-AS1 was transcriptionally induced by hypoxia-inducible factor-1α (HIF-1α), as supported by genetic perturbation, promoter reporter assays, and public ChIP-seq data. Genetic deletion of LGALS8-AS1 suppressed tumor growth and metastatic colonization in vivo, whereas re-expression restored these malignant phenotypes. Integrative analysis of the TCGA-BRCA cohort identified oxidative phosphorylation as the pathway most strongly associated with high LGALS8-AS1 expression. Consistently, loss of LGALS8-AS1 impaired mitochondrial respiratory capacity under hypoxia and reduced the expression of key respiratory chain components, particularly Complex I and IV. Pharmacological inhibition of OXPHOS abolished LGALS8-AS1-dependent growth and invasion. These findings establish LGALS8-AS1 as a hypoxia-responsive metabolic regulator that links hypoxia signaling to mitochondrial function in breast cancer.