Engineering Gossypol‐Free Cottonseeds for Future Global Food Security and Agricultural Sustainability

ABSTRACT Cottonseed, a protein and oil rich byproduct of cotton ( Gossypium spp.) fiber production, represents a valuable but underexploited food and feed resource. Its utilization is severely constrained by the presence of gossypol, a toxic sesquiterpenoid aldehyde that accumulates in seeds but plays a critical defensive role in vegetative tissues. Recent advances in biotechnology have enabled precise manipulation of gossypol biosynthesis and gland formation, offering strategies to decouple nutritional quality from plant defense. Targeted approaches such as CRISPR/Cas9 mediated genome editing, RNA interference (RNAi), and virus‐induced gene silencing (VIGS) have successfully surpassed key regulators, including GoPGF and CGP1 , resulting ultralow gossypol cottonseed (ULGCS) while maintaining protective gossypol levels in leaves and stems. Stable transmission of these traits across generations positions cotton as a dual‐purpose crop that simultaneously provides fiber and safe, high‐quality protein. Integrating ULGCS into food systems could alleviate protein malnutrition, potentially benefiting over 500 million people annually, while also expanding the $7.4 billion global cottonseed oil market. Future research should integrate multi‐omics, precision breeding, genomic selection, and advanced genome engineering to further enhance ULGCS nutritional value, seed composition, and agronomic performance. In addition, assessing metabolic trade‐offs and ecological implications will be critical to ensure long‐term sustainability. Reprogramming cottonseed gossypol content thus represents a transformative strategy at the interface of plant biotechnology, food security, and sustainable agriculture.