Breaking the Growth-Defense Trade-off in Cereal Crops: CRISPR/Cas and Moonlighting Proteins in Biotic Stress Resistance

Recurrent crop disease outbreaks linked to global warming pose challenges to sustainable food production. Conventional plant breeding techniques may become less effective at addressing these threats, as improving disease resistance often causes yield reduction. Amid these challenges, CRISPR/Cas-based gene editing offers targeted and tractable solutions. This review synthesizes recent approaches to uncoupling immunity from productivity in cereals. We show that susceptibility (S) gene disruption can provide resistance without activating costly defense mechanisms. We also discuss the generation of new alleles through targeted modifications that mitigate autoimmunity-associated fitness costs. Here, we propose CRISPR-mediated de-moonlighting, an approach for decoupling multifunctional protein activities. Multiplex editing of minor resistance loci, especially in polyploids such as wheat, offers long-lasting, broad-spectrum protection. These strategies converge on the manipulation of canonical moonlighting proteins, multifunctional signaling hubs, and pleiotropic regulators, which serve as regulatory nodes that link development and immunity. CRISPR-mediated precision modification of these regulators can fine-tune the growth-defense balance. Combining these approaches with systems biology, AI-driven design and advanced breeding pipelines can help develop high-yielding, disease-resistant cereals for sustainable agriculture.