Harnessing natural diversity of Saccharomyces cerevisiae for enhanced resistance to weak acids.

The production of second-generation bioethanol from lignocellulosic biomass is a promising solution for sustainable energy, yet it faces significant challenges also due to the inhibitory effects of weak acids released during biomass pretreatment, particularly acetic, formic and levulinic acids. This review describes the ability of Saccharomyces cerevisiae, with a focus on natural isolates, in overcoming these challenging compounds. Indeed, natural isolates exhibit greater genetic and phenotypic diversity than laboratory and industrial strains, offering unique traits such as enhanced stress tolerance, metabolic efficiency, and adaptive responses to weak acids. This investigation explores the transcriptional and genomic mechanisms underlying yeast adaptive responses, emphasizing key regulatory networks and resistance pathways, including drug H+ antiporters, Reactive Oxygen Species (ROS) mitigation strategies, and membrane composition adjustments. Strategies for strains improvement, involving adaptive laboratory evolution (ALE), genome shuffling, and hybridization, are also discussed as complementary approaches to develop robust yeast capable of thriving under stressful industrial fermentation conditions. The integration of these techniques, along with genomic and transcriptomic insights, provides a comprehensive framework for engineering high-performance yeast strains. Ultimately, this review underscores the potential of leveraging natural diversity and innovative biotechnological strategies to advance the scalability and efficiency of lignocellulosic bioethanol production through S. cerevisiae fermentation.