Biological Detoxification of Gossypol: Enzymatic Mechanisms, System Engineering, and Prospects for Green Valorization

Gossypol is a redox-active, electrophilic polyphenolic aldehyde whose structure-reactivity drives persistent toxicity and limits upgrading of cottonseed coproducts. Existing detoxification methods are often resource-intensive, can erode protein quality, and are still judged mainly by bulk gossypol reduction rather than product-resolved evidence. This leaves a core gap; detoxification cannot be claimed unless transformation products are identified and shown to have reduced bioavailability and hazard. Here, we link gossypol tautomerism and reactive hotspots to tractable targets, consolidate microbial and mixed-culture routes, and classify gossypol-active enzymes into four modules: functional group modification, aromatic ring cleavage, solubility-enhancing conjugation, and radical-mediated cyclization. We synthesize strategies to implement these modules in controllable systems, including enzyme engineering, designed multienzyme cascades, AI-enabled enzyme/pathway mining, and synthetic biology architectures that coordinate flux with redox/cofactor constraints. Finally, we propose product-resolved verification combining analytics, fate tracking, tiered bioassays, and toxicokinetics to define standardizable end points for net risk reduction.