Abstract

Mathematical models of metabolism based on mass-balance constraints are essential for analyzing cellular biochemistry, but their predictions are often compromised by thermodynamically infeasible flux cycles-unrealistic loops of biochemical reactions that circulate continuously without external energy input. Here, we introduce Teraflux, a method that generates transcriptome-specific metabolic flux estimations free of these modynamic consistency. By distinguishing between chemical potentials and reaction rates, it uses flux constraints to encode biological irreversibility without overfitting the chemical potential space. Across diverse cally essential feasible cycles like the glyoxylate shunt, and prevents implausible metabolic states such as tions fundamentally align with physiological limits on intracellular metabolite concentrations. Teraflux provides a robust, computationally efficient tool for obtaining reliable, condition-specific fluxomes.