Technology-enabled insights into SLC transporters in MAFLD: redefining the multi-hit pathogenesis and therapeutic landscape.

Recent advances in structural biology, functional genomics, and artificial intelligence (AI) have expanded understanding of the solute carrier (SLC) transporter superfamily. Emerging evidence indicates that SLC transporters play central roles in the multi-hit pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD). In this review, we build upon the classical "two-hit" hypothesis to summarize how CRISPR-based screening, cryo-electron microscopy (cryo-EM), and AI-driven platforms such as AlphaFold and RosettaVS have advanced the study of SLC transporters. These approaches have enabled the identification of SLCs implicated in MAFLD pathogenesis, including SLC13A5 (NaCT) and SLC25A47, as well as the determination of high-resolution structures that support rational drug design for targets such as sodium-glucose cotransporter 2 (SLC5A2) and monocarboxylate transporter 10 (SLC16A10). In addition, ultra-large virtual screening strategies have accelerated the discovery of small-molecule inhibitors targeting SLC transporters. We synthesize current evidence defining the mechanistic roles of SLC transporters in lipid and glucose metabolism, mitochondrial dysfunction, and gut-liver axis dysregulation. Finally, we discuss therapeutic implications, ranging from clinically repurposed SGLT2 inhibitors to investigational agents such as the SLC13A5 inhibitor ETG5773, and outline future directions for technology-driven precision medicine treating MAFLD.