• Serum starvation triggers apoptosis selectively in high-density MEFs via coordinated HIF-1α activation and JNK suppression.
• HIF-1α is necessary and sufficient for serum deprivation-induced apoptosis, while JNK inhibition mimics the high-density apoptotic phenotype.
• The study reveals a density-dependent apoptotic switch integrating metabolic stress and survival signaling.
• These findings offer potential therapeutic targets for diseases involving aberrant cell survival, such as cancer.