The accelerating impacts of global climate change and the intensifying degradation of the environment have underscored the urgent need for the development of effective strategies to mitigate atmospheric CO₂ levels and enhance carbon recycling (Liu et al., 2023; Liu et al., 2022). Achieving carbon neutrality has emerged as a global imperative; however, the inherent stability of CO₂ molecules presents formidable challenges to their efficient capture, conversion, and utilization (Vitillo et al., 2022). Recent advancements in carbon capture, storage, and utilization (CCU) technologies offer promising solutions to these challenges. By converting CO₂ into valuable chemicals and fuels, these technologies not only mitigate environmental harm but also promote sustainable resource recycling (Akash et al., 2023; Alissandratos et al., 2014). Among the various approaches, biological carbon fixation is considered the most environmentally friendly pathway. For instance, microorganisms like cyanobacteria and sulfur bacteria naturally utilize CO₂ for growth and can convert it into organic compounds (Akash et al., 2023).

Nevertheless, as a gaseous substrate, CO₂ is constrained by gas–liquid mass transfer limitations, and most microorganisms (e.g., bacteria and yeasts) struggle to directly assimilate it as a carbon source, thereby restricting its broader application in biotechnology. Alternatively, converting CO2 into more usable carbon liquid feedstocks such as methanol or formic acid, offers a more viable solution. Formic acid, as a liquid substrate, largely bypasses these mass transfer limitations. Consequently, CO2 can be effectively recycled through its biological utilization and conversion into formate (Cotton et al., 2020; Ünlü et al., 2021). However, the application of formate in microbial systems presents notable challenges due to its toxicity at elevated concentrations, which hampers cell growth and disrupts metabolic processes (Liu et al., 2017).

Formate dehydrogenase (FDH), an enzyme catalyzing the reversible conversion between formate and CO₂, emerges as a promising biocatalyst for CCU applications (Harmer et al., 2023; Maier et al., 2024). In microbial systems, NAD(P)+-dependent FDH plays a critical role by oxidizing formate to generate CO₂, providing reducing power and enhancing microbial tolerance to formate (Mao et al., 2020). In contrast, metal-dependent FDH is characterized by a lower redox potential, making it more favorable for driving the reduction of CO₂ to formate under mild conditions. Notably, recent advances in enzyme engineering have significantly enhanced the ability of NAD(P)+-dependent FDH to catalyze the reverse reaction—from CO₂ to formate—overcoming the naturally weak activity observed in this direction (Alpdağtaş et al., 2022; Çakar et al., 2020). This bidirectional catalytic activity of FDH holds considerable potential for both microbial fermentation and sustainable CO₂ recycling (Fig. 1). However, the current review primarily focuses on the structural attributes, catalytic mechanisms, and CO₂-catalyzing capabilities of FDH, but it lacks a comprehensive examination of its role within biological systems and a detailed analysis of how its bidirectional catalytic function influences microbial processes. Despite the challenge of carbon loss, FDH presents considerable potential to enhance formate tolerance, provide reduced power, and facilitate its application in microbial systems.

This review emphasizes the dual function of FDH in formate metabolism and CO₂ reduction. We highlight its potential for CO₂ mitigation and propose various strategies to address carbon loss, including integrating FDH with carbon fixation pathways, the application of adaptive laboratory evolution (ALE), and the utilization of dynamic metabolic control systems. In addition, we have incorporated and analyzed recent advances and outlined forward-looking perspectives for the rational design of microbial platforms tailored for sustainable carbon cycling. Ultimately, this review seeks to offer both theoretical insights and practical strategies for the design of microbial platforms optimized for formate utilization, thereby contributing to the advancement of sustainable carbon cycling.