Background Chromatin accessibility is widely used as a proxy for transcriptional potential, based on the premise that open chromatin promotes transcription factor binding and gene activation. Techniques such as ATAC-seq are therefore commonly used to predict regulatory activity and link distal elements to gene expression. However, the quantitative relationship between accessibility and transcription remains unclear, particularly under acute cellular stress. Metabolic challenges like nutrient deprivation induce extensive chromatin remodelling and transcriptional reprogramming, raising the question of whether transcriptional output is directly governed by chromatin accessibility in these contexts. Clarifying this relationship is critical for interpreting epigenomic data under stress conditions. Results We conducted integrated chromatin accessibility and transcriptome analyses in human U2OS osteosarcoma cells following 18 hours of severe nutrient deprivation. Starvation induced widespread chromatin compaction, with ~95% of accessible regions showing reduced accessibility across promoters and enhancers. Despite this global reduction, transcriptional responses were selective: approximately 64% of differentially expressed genes were upregulated, indicating predominant gene activation even under compacted chromatin conditions. Correlation analyses showed a weak association between promoter accessibility and gene expression (Pearson r ≈ 0.22), and an even weaker relationship at enhancers (r ≈ 0.08). Less than 7% of regulatory element–gene pairs exhibited concordant changes. Overall, chromatin accessibility explained only ~6% of the variance in transcriptional changes, demonstrating substantial uncoupling between chromatin state and gene expression during acute metabolic stress. Despite this global disconnect, pathway-level analysis revealed selective preservation of key adaptive programmes. Genes involved in extracellular matrix organisation, lipid and cholesterol metabolism, small GTPase signalling, and developmental processes remained transcriptionally upregulated, even as accessibility at their regulatory regions declined. This suggests that essential stress-response pathways can be maintained independently of bulk chromatin accessibility. Conclusions These findings demonstrate that chromatin accessibility and transcription are largely decoupled during acute nutrient deprivation. This challenges the assumption that ATAC-seq reliably predicts transcriptional output under stress and highlights the need for caution when interpreting accessibility data in such contexts. The selective maintenance of adaptive programmes further suggests that stress-responsive gene regulation can operate through mechanisms partially independent of global chromatin state.