Jingyi Qian, Lingling Wang, Liang Guo, Tiantian Chai, Xiulai Chen
The increasing imperative to mitigate greenhouse gas emissions and foster the transition to a low-carbon bioeconomy has intensified interest in methane bioconversion as a sustainable approach for transforming methane into valuable bioproduction. Although advancements have been made in optimizing methanotrophic pathways to improve bioproduction, significant challenges persist, including methane solubility, bioavailability, and metabolic flexibility, limiting the efficiency of methane bioconversion. This review provides a comprehensive overview of the initiatives aimed at developing next-generation methanotrophic cell factories by overcoming the physiological limitations of natural methanotrophs. We first analyze the metabolic characteristics of methanotrophs for assimilating methane into cellular building blocks. Then, we discuss methane assimilation pathways and their unique characteristics in matter and energy transmission for facilitating the integration of methane into central carbon metabolism. Further, we propose a systematic framework for designing methane-based biomanufacturing to enable low-carbon bioproduction by integrating synthetic biology, metabolic engineering, and systems biology, thereby developing efficient methane assimilation cell factories for producing high-value bioproducts. Finally, we prospect the potential for valorizing methane derived from anthropogenic emissions and renewable sources, while identifying the key challenges and future research directions necessary for advancing a sustainable, low-carbon bioeconomy.