Mechanical regulation of cellular energy metabolism in cancer microenvironments

Cells dynamically regulate their morphology, contractility, and metabolism in response to the mechano-chemical properties of their microenvironment. Here, we show matrix stiffness and ligand density jointly govern the bioenergetics of contractile cells through a nonequilibrium active chemo-mechanical model built around a newly introduced cellular metabolic potential. This concept links ATP hydrolysis to mechanosensitive signaling, quantifies the energetic cost of stress fiber assembly, and determines mechanically stable states. The metabolic potential enables quantitative prediction of cell contractility, morphology, and ATP consumption in different stiffness 2D and 3D environments, and we find quantitative agreement with experimental measurements in MDA-MB-231 breast cancer cells. The model further predicts activation of AMPK accompanies increased energetic demands in stiffer microenvironments which we experimentally validate and correlate with increased mitochondrial membrane potential, glucose uptake, and intracellular ATP levels. Together, these findings establish a predictive quantitative framework unifying mechanosensitive control of cell shape and contractility with the metabolic pathways sustaining cellular function across diverse mechanical environments. TeaserMatrix stiffness reshapes the cellular energy budget, driving metabolic adaptation to mechanical demand.