Systems-level regulation principles for microbial lignin valorization

Lignin, the most abundant renewable source of aromatic carbon, holds strong potential for sustainable biomanufacturing. However, the complexity of lignin-derived aromatic compounds from depolymerization imposes significant challenges on the metabolic regulation of cell factories, thereby limiting efficient biological conversion. This review provides the systems-level regulation principles that enable microbial lignin valorization, covering metabolic regulation in microbial cell factories, transcription factor-based regulation, and dynamic biosensor-based regulation. Synthetic biology tools collectively enhance metabolic flux distribution and pathway robustness. Transcription factor engineering enables coordinated multi-gene regulation and improves microbial adaptability to diverse aromatic substrates. Dynamic engineering strategies provide precise, real-time metabolic control. Overall, these regulatory strategies form an integrated framework for improving the robustness, responsiveness, and overall efficiency of lignin-bioconversion cell factories. Looking ahead, the convergence of machine-learning-guided design, systems-level flux reprogramming, and multi-layer regulatory integration is expected to accelerate the development of efficient, adaptive, and industrially scalable lignin valorization platforms.