High-throughput screening for biostimulant discovery: opportunities to enhance nitrogen use efficiency.

Improving plant nitrogen use efficiency (NUE) is essential for reducing fertilizer inputs, costs, and environmental impacts such as nitrate leaching and nitrous oxide emissions. Biostimulants that modulate nitrogen transporters, metabolic enzymes, or signaling regulators hold considerable promise in this regard. However, such biostimulants are largely discovered empirically and rarely act by specifically targeting these NUE-related processes. Despite major advances in structural and mechanistic knowledge in the plant nitrogen uptake, metabolism or signaling machinery, discovery screens that directly target these molecular components for the identification of NUE-enhancing biostimulants have, to our knowledge, rarely been reported. This contrasts with other areas of plant biology, where chemical genetics and high-throughput screening have yielded influential molecular tools and agrochemical leads. This review argues that high-throughput screening represents an untapped opportunity for biostimulant discovery aimed at improving the plant NUE. We outline key conceptual principles of such screening approaches and provide a comprehensive overview of the molecular networks governing nitrogen uptake, transport, assimilation, and signaling. By linking these molecular targets to tractable assay formats and screening strategies, we highlight concrete routes for the discovery of next-generation biostimulants, with a particular focus on small-molecule and other non-microbial products. Together, we aim to inspire the transition from empirical discovery toward mechanism-guided approaches to discover new biostimulants and open routes toward more sustainable, nitrogen-efficient crop production.