Regulatory Pathways of Endophytic Fungi in Promoting Flavonoid Biosynthesis in Medicinal Plants

Endophytic fungi form complex symbiotic associations with medicinal plants via long-term coevolution. Such cross-kingdom interactions substantially modulate flavonoid biosynthesis in host plants. This review dissects the mechanisms through which endophytic fungi elevate flavonoid accumulation in medicinal plants. We first summarize symbiotic and growth-promoting relationships between endophytic fungi and medicinal plants, outlining four core synergistic functions: nutrient supply, phytohormone homeostasis, stress resistance enhancement, and secondary metabolism activation. We then elaborate on three primary regulatory patterns underlying endophyte-modulated flavonoid biosynthesis, including direct activation of plant flavonoid biosynthetic pathways, indirect regulation via stress mitigation and host metabolic reprogramming, and autonomous flavonoid production by endophytic fungi. Notably, most current evidence for autonomous flavonoid biosynthesis by endophytic fungi is derived from axenic cultures, whereas its occurrence and quantitative contribution within colonized plant tissues remain to be established. We further discuss state-of-the-art technologies for untangling plant-fungus symbiotic interactions, including multi-omics integration, spatial metabolomics, single-cell sequencing, synthetic microbial consortia, and CRISPR-Cas genome editing. Lastly, we propose future research perspectives covering green cultivation of medicinal plants, targeted improvement of medicinal quality, and efficient microbial biosynthesis of flavonoids.