Harnessing endophytes and Multi-Omics for sustainable Colchicine biosynthesis.

Gloriosa superba, an endangered medicinal plant, serves as the principal natural source of colchicine, a vital alkaloid used for treating gout, arthritis, cancer, and various inflammatory disorders. However, its conventional extraction from plant tissues is constrained by low yield, ecological degradation, and conservation concerns, necessitating sustainable production alternatives. Emerging evidence indicates that colchicine biosynthesis is not solely plant-autonomous but is strongly influenced by endophytic microorganisms that function as active metabolic partners. Endophytic fungi and bacteria associated with G. superba enhance colchicine accumulation through elicitor-mediated signaling, transcriptional reprogramming, metabolic complementation, and modulation of pathway flux. This review presents a systems-level synthesis that integrates endophyte biology with multi-omics technologies and synthetic biology to redefine colchicine biosynthesis as a coordinated plant-microbe metabolic network. Integrated transcriptomic, proteomic, and metabolomic analyses have enabled mechanistic resolution of the colchicine pathway, including identification of key enzymes, regulatory nodes, and bottlenecks such as the cytochrome P450-mediated oxidative ring expansion central to tropolone alkaloid formation. These insights underpin rational metabolic engineering, CRISPR-based genome editing, and synthetic pathway reconstruction in heterologous microbial hosts. By explicitly linking mechanistic understanding with pathway engineering and biomanufacturing design, this review advances a coherent framework for eco-efficient, scalable colchicine production while supporting conservation of G. superba.