Systems-Level Metabolic Regulation Strategies of Xylose Metabolism in Saccharomyces cerevisiae.

As the second most abundant sugar in lignocellulosic hydrolysates, efficient xylose utilization is critical for achieving high carbon efficiency and economic viability of lignocellulosic fermentation. While heterologous pathway engineering has enabled xylose metabolism in Saccharomyces cerevisiae, xylose fermentation efficiency remains far inferior to glucose, due to imbalanced carbon flux, redox cofactor mismatch, carbon catabolite repression, and signaling pathway‑mediated stress dysregulation, which cannot be resolved by traditional single‑pathway engineering. This review focuses on the conceptual shift from single-pathway construction to system-level metabolic regulation of xylose metabolism in S. cerevisiae. We summarize advances in the optimization of heterologous xylose-assimilation pathways and endogenous metabolic network reprogramming. We then elaborate on non-rational engineering strategies such as adaptive laboratory evolution and synthetic chromosome rearrangement, which uncover hidden regulatory layers and drive the paradigm shift toward system-level design. We further dissect the core global regulatory mechanisms, and their role in coordinating cellular growth, metabolism, and stress tolerance via hierarchical coupling to metabolic networks. By integrating these strategies within a unified regulatory framework, this review provides a systems-level perspective for building efficient and robust xylose-fermenting S. cerevisiae, and offers guiding principles for future lignocellulosic biorefineries targeting multi-substrate utilization.