Lipase Stability in Structured Lipid Synthesis: The Interplay of Substrate Characteristics and Strategies to Improve Its Operational Performance—A Critical Review

Structured lipids (SLs) have attracted growing industrial interest due to their associated health benefits. Lipases, as highly selective and versatile biocatalysts, are central to the sustainable synthesis of SLs attributed to their ability to operate under mild reaction conditions. However, the limited operational stability of lipases remains a major bottleneck, directly affecting process efficiency, product yield, and economic feasibility. While considerable attention has been devoted to enzyme engineering and process optimization, the influence of lipid substrate characteristics on lipase stability has received comparatively little scrutiny. This review critically examines feedstock properties, such as oxidative status, free fatty acid composition, and water activity, that affect lipase performance and deactivation during SL synthesis, where unoptimized substrate characteristics have been shown to reduce lipase stability by two‐ to sevenfold. It further discusses mitigation strategies, including substrate pretreatment with protein, adsorbents, and antioxidant, as well as process design enhancements, which have demonstrated up to sevenfold extensions in operational stability. This review highlights the importance of integrating substrate quality management into biocatalytic process design to enhance lipase operational stability and reusability. By elucidating the interplay between substrate properties and enzyme stability, this work provides a foundation to promote the valorization of nontraditional lipid sources, such as agro‐industry by‐products and underutilized oils, within circular bioeconomy frameworks, thereby supporting the development of more flexible, robust, cost‐effective, and scalable biocatalytic processes for SL production.