Antioxidants by nature: an ancient feature at the heart of flavonoids' multifunctionality

Early land plants’ ability to adapt to novel environmental pressures associated with an ever-changing terrestrial habitat was the result of a vast set of evolutionary innovations, including metabolic ones (Wagner, 2011; Bowman et al., 2017). Land plants, as sessile organisms, were driven to evolve integrated and modular metabolic pathways. Several of them were true metabolic network innova- tions, responsible for synthesizing several novel compounds (Cannell et al., 2020; Dadras et al., 2023b). The new specialized metabolites (SMs) contributed to thrive in these new and frequently hostile environments (Rensing, 2018; Cheng et al., 2019; Han et al., 2019; Buschmann, 2020; F€urst-Jansen et al., 2020). There is evidence that metabolic plasticity is a key component of a highly complex network in the plant–environment interaction, which also includes morphoanatomical traits. This network largely and ultimately determines the ability of terrestrial plants to escape from the most severe environmental threats, the so- called ‘flight strategy’ of sessile organisms (Potters et al., 2007; Lauder et al., 2019). While an elaborate metabolic system was already placed in the closest algal ancestors of land plants (Rieseberg et al., 2021; Dadras et al., 2023a), primary and particularly secondary metabolic networks have grown far more sophisticated throughout plant evolution (Keeling et al., 2010; Wang et al., 2015; Maeda, 2019; Bowles et al., 2020; Li et al., 2024). They contributed to land plant distribution toward more challenging habitats (Steemans et al., 2009). For instance, the R2R3MYB family of transcription factors (TFs), which regulates a wide array of biological processes, including the expression of genes involved in the biosynthesis of phenylpropanoids, has been extraordinarily expanded and diversified in the lineage of angiosperms (Feller et al., 2011; Bowman et al., 2017; Albert et al., 2018; Jiang & Rao, 2020; Davies et al., 2021). Enzymes involved in both the ‘decoration’ of basic phenylpropanoid skeletons (e.g. the C6-C3- C6 core skeleton of flavonoids) and their transport to different subcellular compartments have also expanded much throughout plant evolution (Kitamura, 2006; Tohge et al., 2018; Alseekh et al., 2020; Davies et al., 2020; Li et al., 2020; Wen et al., 2020). The extraordinary chemical diversity originated from the rise and evolution of multiple SM pathways, coupled with their location in different tissues and cellular compartments, well explains the outstanding plant adaptability to harsh stressful conditions (sensu stricto, that is, distance from pre-existing homeostasis) associated with the terrestrial habitat (Fu€rst-Jansen et al., 2020; Rensing, 2020). The pivotal role of SMs in the adaptability of land plants depends not only on their extraordinarily high number and diversified skeletons, synthesized by different taxa (Weng et al., 2021), but also on their inherent ability to play multiple functions (Milo & Last, 2012; Ehlers et al., 2020; Mutwil, 2020; Dur an-Medina et al., 2021; Hu et al., 2021; de Vries et al., 2021; Weng et al., 2021). Although SM biosynthesis might have served as a sink for the excess of carbon available to plants during their initial exploration of a highly enriched CO2 atmosphere (Dadras et al., 2023a,b), SMs multifunctionality efficiently compensates for the energetic cost required for their biosynthesis (Klieben- stein, 2013; Erb & Kliebenstein, 2020). The multifunctional nature of SMs and their high responsiveness to abiotic and biotic stressors provide plants with an unlimited defense arsenal, in which each SM may play different roles depending on the severity of the stress events and the degree of plant body complexity. These factors determine the metabolite distribution at the organ, tissue, cellular, and subcellular levels (Schneider et al., 2019; Wang et al., 2019; Shitan & Yazaki, 2020; Weng et al., 2021). In simpler terms, the evolution of multifunctional SM biosynthesis follows the natural tendency to catch as many flies with one clamp as possible (Wink, 1999; Izhaki, 2002). Here, we focus on the ancient and ubiquitous class of flavonoids (Fig. 1), which are highly responsive to abiotic and biotic environmental stressors and are capable of regulating key steps in plant growth and development (Pollastri & Tattini, 2011; Schneider et al., 2019; Chapman & Muday, 2021; Garagounis et al., 2021; Venegas-Molina et al., 2021; Daryanavard et al., 2023). However, their multifunctionality makes it difficult to determine the foremost environmental drivers for the emergence and diversification of the flavonoid metabolic network, despite decades of extensive research (Rozema et al., 1997, 2002; Buer et al., 2010; Tripp et al., 2018; Yonekura-Sakakibara et al., 2019; Davies et al., 2020). We provide a detailed analysis of the complex relationship between the multifunctional nature of flavonoids and the environmental stimuli primarily responsible for the rise of the flavonoid metabolic network, offering conclusive evidence for the structural–functional relationship that is at the root of their functional versatility.