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

## TL;DR

This review explores how metabolism actively influences tooth development by interacting with key signaling pathways, beyond just providing energy.

## Contribution

The paper introduces a novel framework showing that metabolism actively programs tooth development through bidirectional interactions with developmental pathways.

## Key findings

- Metabolic status engages in bidirectional crosstalk with developmental pathways like Wnt, BMP, FGF, and Hh.
- Metabolism influences cell behavior, tooth morphogenesis, and matrix mineralization in a spatiotemporal manner.
- Hereditary and acquired metabolic disorders highlight the relevance of this network in health and disease.

## Abstract

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.