A Comprehensive Review on the Pharmacological Activities and Biosynthetic Strategies of Protocatechuic Acid.

Protocatechuic acid (PCA) is a simple natural phenolic acid widely distributed in plants. It is recognized as an active constituent of numerous traditional herbal medicines and serves as an important metabolic intermediate of polyphenolic compounds such as anthocyanins and proanthocyanidins. At present, PCA production relies on plant extraction and microbial fermentation. Among these, microbial fermentation has emerged as an attractive approach for industrial development owing to its process controllability, environmentally benign nature, and potential for high productivity. This review systematically summarizes the major pharmacological properties of PCA, including its antioxidant, anti-inflammatory, antimicrobial, antiviral, anti-aging, neuroprotective, and hepatoprotective activities. It further highlights the therapeutic potential of PCA in the prevention and management of various chronic diseases, such as cancer, diabetes, Alzheimer's disease, and hypertension. Furthermore, this review summarizes the representative microbial biosynthetic pathways for PCA and discusses recent progress in metabolic engineering strategies aimed at enhancing its microbial production. These strategies include reinforcing precursor supply, redirecting metabolic flux toward the shikimate pathway, blocking PCA degradation routes, relieving intracellular feedback regulation, improving host tolerance, and optimizing fermentation processes to achieve higher PCA productivity and yield. Finally, the major bottlenecks limiting PCA biomanufacturing are discussed, and prospective directions for future research are proposed.