Ubiquitous Asymptotic Robustness in Biochemical Systems

Living systems maintain stable internal states despite environmental fluctuations. Absolute concentration robustness (ACR) is a striking homeostatic phenomenon in which the steady-state concentration of a molecular species remains invariant to changes in total molecular supply. Although experimental studies have reported approximate-but not exact-robustness in steady-state concentrations, such behavior has often been attributed to exact ACR motifs perturbed by measurement noise or minor side reactions, rather than recognized as a structural property of the network itself. In this work, we highlight a previously underappreciated phenomenon, which we term asymptotic ACR (aACR): approximate robustness can emerge solely from the architecture of the reaction network, without requiring parameters being negligible or the presence of an exact ACR motif. We find that aACR is far more common than classical ACR, as demonstrated in systems such as the Escherichia coli EnvZ-OmpR system and MAPK signaling cascade. Furthermore, we mathematically prove that such ubiquity stems solely from network structure. Finally, we reveal a counterintuitive feature of aACR in systems with multiple conserved quantities, revealing subtle distinctions in how robustness manifests in complex biochemical networks.