How plants make aspirin
When I started working with willow mid 2013, I was surprised that it was still unknown how plants make salicylic acid, a.k.a. the precursor of aspirin. Tea of willow bark, amongst others, is used for centuries before in 1828 the German scientist Johann Buchner extracted a willow-derived compound called salicin, which later came on the market as aspirin.
In 2001 the starting point of the pathway for salicylic acid production in the model plant Arabidopsis was found. But this turned out to be brassica specific. Now not one but three research groups out of China, with some collaboration with US and Canadian researchers, found out how the rest of the plants make salicylic acid.
Salicylic acid is not only a precursor to aspirin, but also an important signalling molecule involved in plant immunity. It functions like a manager or regulator activating and steering the immune response when there is an infection. Knowing how salicylic acid is made therefore can help breeders to develop plants that are better protected against pathogens.
So how did the researchers discover the pathways? Each of the three groups used a different approach. Two of them worked out the production of salicylic acid in rice, which has even under non-infected conditions high levels of the stuff. The third group used Nicotiana benthamiana as a model to figure out the pathway. I can’t go into details of how the third group elucidated the pathway, as their article is behind a paywall. But here they are for the other two.
Approach #1
The tactic if the first group was to find out which genes showed a co-expression profile with one of the genes early in the pathway known to ultimately lead to salicylic acid production. They identified the subsequent genes based on the predicted enzymatic function they needed to perform. Followed by checking if the enzyme produced by the gene indeed worked as expected.
The main hurdle in this process, was the earlier suggestion that benzoic acid is direct precursor of salicylic acid. On paper this is not too far-fetched. The only difference between the two molecules is a hydroxy (-OH) group that salicylic acid has attached to it ring. But the actual pathway did not appear to be that simple.
To find out if the synthesis route goes via benzoic acid the researchers analysed the levels of benzoic acid and salicylic acid. They did this for each of the different mutants that are defect in the early steps of the pathway. In addition, using those same mutants, the researchers did a feeding study to see if intermediate products could restore salicylic acid and benzoic acid levels. Finding that while salicylic acid levels could be restored in the mutants using the feeding approach, those of benzoic acid could not.
Approach #2
The approach of the second group nicely complements that of the first group. They identified mutant plants that did no longer produce salicylic acid. Subsequently they identified the genes responsible for the mutation. Followed by the confirmation of the function of the identified enzymes.
Like the first group this group assumed that benzoic acid was a precursor of salicylic acid. They tested for that with the enzymes identified in the mutant screen. And like the first group they found that actually, the pathway is slightly different.
After having found the enzymes responsible for the different steps of the pathway, both groups checked their presence in other plants. Finding that all of the discovered enzymes are present in most of the plants with exception of the brassicas, to which Arabidopsis belongs.
With the unravelling of this pathway, salicylic acid for aspirin can now be produced in a biological way. But more importantly, it also gives breeders a starting point in developing plants that are more broadly protected against pathogens.
Literature
Wang, Y., Song, S., Zhang, W. et al. Deciphering phenylalanine-derived salicylic acid biosynthesis in plants. Nature (2025). https://doi.org/10.1038/s41586-025-09280-9
Zhu, B., Zhang, Y., Gao, R. et al. Complete biosynthesis of salicylic acid from phenylalanine in plants. Nature (2025). https://doi.org/10.1038/s41586-025-09175-9
Liu, Y., Xu, L., Wu, M. et al. Three-step biosynthesis of salicylic acid from benzoyl-CoA in plants. Nature (2025). https://doi.org/10.1038/s41586-025-09185-7
Plant en Zo 