Editing a single gene unlocks new strategy for sustainable resveratrol supply

Resveratrol, a plant-derived compound celebrated for its antioxidant and therapeutic potential, has long been limited by scarce natural availability and costly production methods. In this study, researchers used CRISPR/Cas9 gene editing to target CHS2 in Vitis davidii cells, disrupting flavonoid synthesis and redirecting metabolic flux toward resveratrol. The edited cell lines accumulated significantly more resveratrol and its derivatives, while showing reduced levels of anthocyanins and other flavonoids. This discovery not only highlights the metabolic competition between flavonoids and stilbenoids but also provides a practical strategy for enhancing natural resveratrol yields. The findings suggest new opportunities for developing plant-based biofactories for high-value nutraceuticals.

Resveratrol is a polyphenolic stilbenoid known for its health benefits, including anti-inflammatory, anti-aging, and anti-cancer effects. However, it occurs naturally in only a handful of plants such as grapes, knotweed, and peanuts, and in very low concentrations. Commercial production has faced hurdles: chemical synthesis introduces impurities, while microbial fermentation often suffers from byproduct contamination and reduced bioactivity compared to plant-derived compounds. Extraction from plants is resource-intensive and inefficient. Given these barriers, scientists have increasingly turned to genetic engineering and plant cell factory approaches to optimize production. Due to these problems, there is a pressing need to explore alternative strategies for sustainable and efficient resveratrol biosynthesis.

A research team from the Fujian Academy of Agricultural Sciences and Shanghai Jiao Tong University reported (DOI: 10.1093/hr/uhae268) a major advance on January 1, 2025, in Horticulture Research. Using CRISPR/Cas9 editing, they disrupted the CHS2 gene in grape cells, revealing how this modification suppresses flavonoid pathways while enhancing stilbenoid synthesis. The study demonstrates how targeted gene manipulation can efficiently boost resveratrol accumulation in plant cell systems. By uncovering a clear shift in metabolic competition, the researchers provide new insight into natural product regulation and open pathways for developing scalable resveratrol production.

The team generated two mutant cell lines of Vitis davidii using CRISPR/Cas9 to edit CHS2, a key enzyme in flavonoid biosynthesis. Mutations introduced premature termination in protein translation, effectively knocking out CHS2. Phenotypic analysis showed reduced anthocyanin pigmentation, consistent with suppression of flavonoid synthesis. High-throughput amplicon sequencing confirmed multiple mutation types, with nearly complete CHS2 knockout in one line.

Metabolomic profiling revealed striking changes: in mutant cells, 72 flavonoids were significantly downregulated, while stilbenoid compounds such as resveratrol, piceid, and pterostilbene were markedly increased. Quantitative assays showed resveratrol levels up to 4.1-fold higher than wild type, and piceid up to 5.3-fold higher. Transcriptomic and RT-qPCR analyses further confirmed that genes involved in flavonoid biosynthesis (including CHS3, F3H, DFR, FLS, LDOX) were downregulated, while multiple STS genes critical for stilbenoid synthesis were upregulated. These findings demonstrate that disrupting CHS2 successfully rerouted metabolic flux from flavonoids to stilbenoids, providing direct evidence of pathway competition. This integrated analysis across genetics, metabolomics, and transcriptomics highlights a powerful new strategy for enhancing specific plant secondary metabolites.

“By knocking out CHS2, we effectively shifted the balance of grape cell metabolism toward resveratrol accumulation,” said lead author Dr. Gongti Lai. “This work not only confirms the competitive relationship between flavonoid and stilbenoid pathways but also demonstrates the potential of targeted gene editing in creating plant cell factories. Compared with conventional production routes, our approach offers a cleaner, more sustainable method of generating resveratrol, which could greatly benefit industries ranging from nutraceuticals to functional foods.”

This study establishes gene editing as a practical route to overcome longstanding challenges in resveratrol supply. By demonstrating that metabolic flux can be redirected from pigments to bioactive stilbenoids, it offers a sustainable alternative to chemical synthesis and microbial fermentation. Scaled production using engineered grape cells could support the growing demand for resveratrol in pharmaceuticals, cosmetics, and health supplements. Moreover, the strategy exemplifies a broader application: tailoring plant metabolic pathways to enhance desirable compounds while suppressing unwanted traits. Such precision engineering could accelerate the development of new crop varieties and natural product platforms with significant economic and health value.

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References

DOI

10.1093/hr/uhae268

Original Source URL

https://doi.org/10.1093/hr/uhae268

Funding information

This work was founded by National Natural Science Foundation of China (32302284), Natural Science Foundation of Fujian Province, China (2021 J05091), High Quality Development “5511” Collaborative Innovation Project between Fujian and Chinese Academy of Agricultural Sciences (XTCXGC2021014), and Fujian Provincial Department of Science and Technology of Special Public-funded Projects (2021R1032009).

About Horticulture Research

Horticulture Research is an open access journal of Nanjing Agricultural University and ranked number one in the Horticulture category of the Journal Citation Reports ™ from Clarivate, 2023. The journal is committed to publishing original research articles, reviews, perspectives, comments, correspondence articles and letters to the editor related to all major horticultural plants and disciplines, including biotechnology, breeding, cellular and molecular biology, evolution, genetics, inter-species interactions, physiology, and the origination and domestication of crops.