Multilevel Mechanisms by Which Membrane Transport Proteins Regulate Plant Responses to Heavy Metal Stress: From Ion Perception and Uptake Control to Systemic Signaling and Translational Perspectives

ABSTRACT Soil heavy metal contamination—including cadmium (Cd), arsenic (As), lead (Pb), mercury (Hg), zinc (Zn) excess, and copper (Cu) excess—poses a critical threat to sustainable agriculture and food safety. Membrane transport proteins serve as primary interfaces governing ion entry, subcellular compartmentalization, and long‐distance redistribution. This review integrates recent advances across multiple scales to construct a unified regulatory framework: (i) at the cell periphery, plasma membrane transporters of the NRAMP, ZIP, and COPT families mediate metal influx, whereas efflux transporters and cell wall modifications limit cytosolic accumulation; (ii) at the subcellular level, vacuolar HMA and ABCC transporters drive sequestration, coordinated by COPII‐mediated forward trafficking, ESCRT‐dependent turnover, and autophagy‐based quality control; (iii) at the signaling level, Ca 2+ ‐ROS‐MAPK cascades and lipid microdomain dynamics modulate transporter activity through phosphorylation and endocytic sorting; and (iv) at the whole‐plant level, xylem‐phloem transport and systemic signals (Ca 2+ waves, ROS, jasmonic acid) coordinate root‐shoot communication. The strength of evidence distinguishing in planta validation from heterologous inference is critically evaluated, the biological trade‐offs associated with transporter manipulation are addressed, and species‐specific strategies contrasting hyperaccumulators with low‐accumulation food crops are discussed. Finally, the potential of cryo‐electron microscopy (cryo‐EM), single‐cell transcriptomics, genetically encoded sensors, and rhizosphere engineering in reshaping this field is outlined. This synthesis aims to provide a roadmap for developing crops with low metal accumulation and high stress tolerance through precision breeding and gene editing.