Salicylic acid (SA), an ancient anti-inflammatory component derived from willow bark, is not only a natural precursor to aspirin but also a core defense hormone in plants against pathogen invasion. However, its biosynthetic pathway within plants has long been a mystery, especially the key synthesis mechanism in non-cruciferous plants, which has remained unresolved for decades.
On July 23, 2025, Professo Yuelinr Zhang's team from Sichuan University published a research paper in Nature entitled "Three-step biosynthesis of salicylic acid from benzoyl-CoA in plants," revealing for the first time a completely new salicylic acid synthesis pathway—the PAL/BSH pathway. This research not only fills a key gap in the map of plant hormone synthesis but also confirms that this pathway is widely present and highly conserved in seed plants, marking a milestone in the study of plant disease resistance mechanisms.
It is worth mentioning that this is another major breakthrough in salicylic acid synthesis achieved by Yuelinr Zhang's team, following their successful analysis of key steps in the isochorismate synthase (ICS) pathway of Arabidopsis thaliana in Science in 2019. Reaching the top of the international journals twice within just six years fully demonstrates the team's leading position in the global field of plant hormone research. In May of this year, the team, in collaboration with Professor Xin Li's team from the University of British Columbia, published a research paper in Science entitled "Distribution of haploid chromosomes into separate nuclei in two pathogenic fungi," revealing an unprecedented fungal chromosome allocation mechanism that overturns fundamental understandings in traditional genetics and cell biology.
For a long time, the synthesis of salicylic acid in plants has been thought to mainly rely on two pathways: the ICS pathway and the phenylalanine ammonia-lyase (PAL) pathway. The mechanism of the ICS pathway in the model plant A. thaliana has been largely elucidated. However, increasing evidence suggests that in non-cruciferous plants such as rice, soybean, and tobacco, the PAL pathway plays a dominant role in pathogen-induced SA accumulation. Although early isotope tracing experiments suggested that benzoic acid (BA) might be an important intermediate in this pathway, the benzoic acid 2-hydroxylase (BA2H), which catalyzes the conversion of BA to SA, has remained unidentified, becoming a major unsolved problem in the field for decades.
To solve this challenge, Yuelin Zhang's team employed a multidisciplinary approach, integrating chemical genetic screening, transcriptome analysis, CRISPR gene editing, and high-precision metabolic detection technologies. They successfully traced and reconstructed the complete reaction chain of the PAL pathway in Nicotiana benthamiana. The research unexpectedly discovered a previously unknown three-step enzymatic cascade reaction:
This indirect synthetic strategy overturns traditional understanding, explaining why directly searching for BA2H has been unsuccessful—nature achieves the conversion of BA to SA through a clever "esterification-hydroxylation-hydrolysis" circuitous pathway.
Figure 1. The biosynthetic pathway of salicylic acid. (Liu, et al. 2025)
Through phylogenetic analysis, cross-species functional complementation experiments (such as restoring salicylic acid (SA) synthesis in rice mutants), and pathogen infection response tests, the research team further confirmed that the PAL/BSH pathway is ubiquitous and highly conserved in various important crops and forest trees, including rice, soybean, willow, and poplar. This indicates that this pathway is a universal mechanism of disease resistance defense systems in seed plants, rather than a species-specific exception.
This achievement not only completely resolves the long-standing controversy surrounding the SA synthesis mechanism in the PAL pathway but also provides crucial molecular evidence for understanding the evolutionary differences in disease resistance strategies among different plant groups. More importantly, the three newly discovered key enzymes—BEBT, BBO, and BSH—open up entirely new targets for crop disease resistance breeding. In the future, gene editing or expression regulation can be used to precisely enhance the salicylic acid synthesis capacity of crops, thereby improving their broad-spectrum disease resistance and reducing pesticide dependence. Furthermore, this research provides theoretical support for the efficient biosynthesis and metabolic engineering optimization of salicylic acid-based active ingredients in medicinal plants, demonstrating significant application prospects.
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