Cells can deal with different kinds of stress by responding with compensatory or detoxifying mechanisms. Only when such systems become saturated or overstrained, the stress may emerge as toxic. In energy metabolism, the AMP-activated protein kinase (AMPK) has evolved to detect physiologically relevant energy stress in form of decreased ATP/AMP and ATP/ADP ratios. Once activated, AMPK induces compensatory measures that increase ATP generation and reduce ATP consumption. We have exploited this naturally evolved energy sensing mechanism by engineering the genetically-encoded, FRET-based nanosensor AMPfret. This sensor allows for direct, real-time monitoring of cellular energy state as the cell perceives it. We now developed clonal cell lines with site-specific integration of the AMPfret genes, showing AMPfret expression at suitable levels (Abi Nahed et al., 2023, Meth Mol Biol). With the example of HEK293T cells treated with nanoparticles or prospective anti-cancer drugs, we show that the early time course of the AMPfret signal is predictive for physiological versus toxic stress. While the former leads to only mild or transient increase in the AMPfret signal, the latter triggers a possibly slow but persistent and strong increase in AMPfret signal. Thus, AMPfret seems to be appropriate for a more generalized energy-linked toxicity screening.