18β-glycyrrhetinic acid breaks the growth-immunity trade-off via selective suppression of adaptive immunity

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Abstract
Background: While the growth-immunity trade-off has been extensively studied in plant biology, its existence, underlying immunometabolic mechanisms, and practical implications in animals remain poorly characterized. Chronic immune activation diverts essential bioenergetic resources away from somatic development, highlighting a critical need for interventions capable of modulating this physiological balance. The potent anti-inflammatory properties of 18β-glycyrrhetinic acid (GA), an active component of licorice, provide a unique opportunity to elucidate this regulatory mechanism. Methods: To elucidate the regulatory logic of this trade-off in ruminants, we integrated large-scale physiological profiling, multi-tissue bulk transcriptomics, single-cell RNA sequencing (scRNA-seq), limited proteolysis-coupled mass spectrometry (LiP-MS), and molecular docking. We evaluated a large lamb cohort (n = 448) to determine the systemic and molecular effects of maternal 18β-glycyrrhetinic acid (GA) supplementation on offspring. Results: Gestational GA administration significantly dampened systemic inflammatory tone and oxidative stress, redirecting metabolic resources to somatic growth. This resulted in marked improvements in offspring birth weight (by 7.09%), weaning weight (by 10.66%), skeletal muscle fiber development, and secondary hair follicle maturation. Inter-tissue communication analysis pinpointed the lymph node as the primary signaling hub for GA-mediated inter-organ regulation. Specifically, scRNA-seq revealed that GA preferentially acts on adaptive T-cell subpopulations within the lymph nodes. Furthermore, LiP-MS and molecular docking identified key NF-κB pathway components—specifically PARP1, DDX1, RIPK1, HSPA1A, FLOT1, FLNA, REL, and TRADD—as direct physical binding targets of GA. By engaging these molecular targets, GA suppresses hyperactivated NF-κB signaling in T cells, reducing pro-inflammatory cytokine production and the bioenergetic costs of immune maintenance. Conclusion: This study establishes the operational animal growth-immunity trade-off paradigm and demonstrates that maternal GA intervention successfully optimizes livestock growth performance and systemic homeostasis through precise immunometabolic regulation.

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