A Systems View of Ganoderma Triterpenoids Biosynthesis: Signals, Transcription, and Biosynthetic Remodeling

Ganoderma triterpenoids (GTs), the major bioactive metabolites of Ganoderma lucidum, are widely known for their pharmaceutical versatility. However, their natural biosynthesis ability is insufficient to meet industrial demands, so it is urgently required to clarify the metabolic network of GTs and develop new strategies to increase the total GTs production. Recently, the complex multi-tiered regulatory framework, which includes the sequential integration of environmental perception, signal transduction, and transcriptional reprogramming, has been fully dissected. This review synthesizes recent breakthroughs that illustrate how environmental stimuli are transduced through independent or intricate spatiotemporal interactions involving reactive oxygen species (ROS), calcium ions (Ca2+), and nitric oxide (NO). Such interplays give rise to oscillatory or feedback loops that precisely modulate metabolic production. Moreover, we systematically examine various transcription factors that control metabolic fluxes by either directly targeting the rate-limiting enzymatic steps of the mevalonate (MVA) pathway and downstream CYP450-modification networks, or via epigenetic and complex-mediated pathways. Importantly, we consider the application of gene editing, AI/ML-guided enzyme engineering, and subcellular compartmentalization as innovative ways to overcome their yield bottlenecks. Successful heterologous construction of biosynthetic pathways highlights the continuing trend towards predictability in biomanufacturing. In summary, this review presents a holistic translational approach from foundational regulatory mechanisms to synthetic assembly, establishing G. lucidum as a viable and intelligent bio-manufacturer for producing high valuable GTs.