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.

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, Ca2+-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 (Ca2+ 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.