Metabolic programming in tooth development: a regulatory network from energy substrates to signaling instructions.

Tooth development is a process meticulously orchestrated by complex signaling networks. Traditionally, metabolism has been viewed as a passive supplier of energy and building blocks. This review, by systematically integrating recent evidence, proposes that metabolism acts as an active programmer during tooth development, whose functions extend beyond fundamental support. We elaborate a dynamic metabolic regulatory framework wherein cellular metabolic status engages in deep, bidirectional crosstalk with classic developmental pathways such as Wnt, BMP, FGF, and Hh through four core mechanisms: energy sensing and fate decision, moonlighting signaling functions of metabolic enzymes, metabolite-mediated epigenetic remodeling, and specific substrate metabolism. This crosstalk guides cell behavior, tooth morphogenesis, and matrix mineralization in a spatiotemporally specific manner. Evidence from models of hereditary or acquired metabolic disorders strongly underscores the physiological and pathological relevance of this network. Building on this integrative perspective, we further discuss how emerging technologies-including spatial multi-omics, organoids, and computational modeling-can deepen mechanistic understanding, and explore the translational potential of targeting metabolic nodes for early diagnosis, prevention, and regenerative therapy. This review aims to provide a systematic discussion on the central regulatory role of metabolic status in tooth development, with a focus on the metabolism-signaling integrative network, thereby offering a more comprehensive conceptual framework for elucidating developmental principles, disease mechanisms, and informing novel strategies in oral medicine.