Targeting DOPA decarboxylase disrupts immune‐metabolic coordination and renders Spodoptera frugiperda susceptible to bacterial infection

DOPA decarboxylase (DDC) is a key enzyme that connects melanin production and innate immunity in insects, yet its regulatory network in major lepidopteran pests remains poorly understood. We combined CRISPR/Cas9 gene editing with multi-omics analysis to explore DDC's role in immune responses in the invasive pest Spodoptera frugiperda. Knocking out DDC caused complete albinism, severe developmental delays, pronounced developmental defects, and increased susceptibility to bacterial challenge. Following the E. coli challenge, DDC-mutant larvae showed substantially lower final survival than infected wild-type larvae (6.7% vs. 66.7%) and failed to pupate, despite pronounced cuticular darkening. Transcriptomic and metabolomic analyses showed that DDC loss disrupted the tyrosine-dopamine pathway and was associated with altered expression of genes related to the prophenoloxidase cascade. Notably, laccase2 was transcriptionally upregulated after challenge; however, its contribution to infection-associated cuticular darkening remains to be determined. This response did not restore dopamine-dependent immune signaling or whole-body metabolism, as evidenced by disruptions in glycine/serine pathways and reduced immune gene activity. These results separate pigmentation from immune functions within the melanin pathway, highlighting DDC as a crucial immune-metabolic hub. Given its roles in development and immunity and the high conservation of the dopamine pathway in invertebrates, DDC is a promising target for species-specific, resistance-proof RNAi pest control methods.