ABCG and ABCH transporters at the interface of cuticular lipid transport and insecticide handling

ATP-binding cassette (ABC) transporters are widely associated with insecticide resistance, yet the physiological links between endogenous transport and xenobiotic handling remain incompletely resolved for ABCG and arthropod-associated ABCH subfamilies. Unlike many canonical full ABC transporters, ABCG and ABCH proteins usually have reverse half-transporter topology and require dimeric assembly, creating substrate-recognition spaces that can support lipid movement, pigment precursor routing, cuticular barrier formation, and chemical-response phenotypes. Here, we synthesize structural, physiological, and toxicological evidence from insects and mites to evaluate how these transporters may connect cuticular lipid homeostasis with insecticide handling. Recent structural work on Tribolium castaneum TcABCH-9C supports an ATP-coupled squeeze-pump model for hydrophobic substrates, including ceramide-like lipids and fenoxycarb. This model provides an important mechanistic framework, but its direct support is currently limited to one ABCH system and should not be generalized to all ABCH orthologs or to ABCG transporters without comparative validation. We distinguish three experimentally separable interaction modes: competitive occupancy, spatial blockade, and functional uncoupling. Because direct proof that endogenous lipids and insecticides compete within the same transporter cycle remains limited, we propose an evidence-tier framework that integrates structural, biochemical, physiological, and genetic validation. Finally, we discuss how RNA interference, CRISPR/Cas9, and structure-guided perturbation can support functional testing while remaining constrained by delivery, specificity, field feasibility, and non-target arthropod safety.