Sustainable Cultivation of Rare and Endangered Medicinal Plant Multicellular Spheroids Producing Bioactive Therapeutics for Alcohol‐Related Liver Disease Therapy

Plant-based biomaterials, prized for their inherent biocompatibility and biodegradability, serve as excellent candidates for biomedical applications. This is largely due to the unique pharmacological properties of their bioactive metabolites. However, the sustainable and economical production of these metabolites, particularly from rare and endangered species, remains challenging. In this study, we developed a multicellular spheroid-based cultivation strategy using medicinal plant cells to efficiently produce bioactive metabolites, exemplified by the endangered species Saussurea involucrata (SI). Optimized culture conditions stimulate sustainable production of SI-derived secondary metabolites (SIM) enriched with antioxidant and anti-inflammatory constituents. Single-cell transcriptomics identify nine functionally specialized cell clusters responsible for the biosynthesis of pharmacologically active constituents. Ultra-high performance liquid chromatography-MS/MS catalogs 679 metabolites, with a chemical profile closely resembling that of wild SI. Network pharmacology links SIM to 318 therapeutic targets relevant to alcohol-associated liver disease (ALD). In vitro, SIM decreases reactive oxygen species, suppresses hepatocyte apoptosis, and attenuates macrophage-mediated inflammation. In an ALD mouse model, SIM administration alleviates hepatic lipid accumulation, restores liver function, and favorably remodels the gut microbiota. Together, these results establish a sustainable biomanufacturing paradigm for bioactive compounds from rare medicinal plants and highlight SIM as a promising candidate for ALD therapy.