Advances in transcription factor-based biosensors for natural product biosynthesis: Optimization, emerging technologies, and future prospects.

Natural products (NPs) are increasingly applied in food, medicine, and biotechnology. However, their biosynthesis remains constrained by low titers and yields. Transcription factor-based biosensors (TFBs) can convert biological signals into measurable outputs, enabling real-time monitoring and dynamic regulation of biosynthetic pathways, thereby facilitating the overcoming of these limitations. This review highlights recent advances in applying TFBs to NP production, with a focus on high-throughput screening, adaptive evolution, and dynamic control. We further discuss innovative engineering approaches aimed at optimizing TFB performance, including in silico TF identification, protein engineering, and fine-tuning of regulatory elements. Finally, we examine the challenges associated with using TFBs for microbial NP production and explore their potential in emerging platforms such as cell-free systems and non-model microorganisms. These insights offer valuable perspectives on overcoming the current limitations of biosensing technologies and advancing the scalable production of NPs.