To survive and maintain normal function, cells must closely monitor and control intracellular substances. By allowing specific molecules such as metabolites and ions to pass through the lipid bilayer and enter or leave the cell, transporters control nutrient levels, remove intracellular waste, and regulate cell volume. Different types of transporters can be subdivided into four major superfamilies: a. ATP-binding cassette (ABC) transporters, b. ATPases, c. ion channels, and d. solute carrier proteins (SLCs).

（Data source: Reactome）

The SLC superfamily currently encompasses 458 transporters in 65 families. They facilitate the transport of a wide variety of small molecules across biological membranes, controlling fundamental physiological functions from nutrient uptake to drug absorption and disposal. The average SLC subfamily contains seven members, with eight subfamilies containing only one member (SLC32, SLC40, SLC48, SLC50, SLC53, SLC61, SLC62, and SLC64). The largest subfamily, SLC25, comprises 53 members.

（Data source: Zhang Y, et al. J Mol Cell Biol. 2019）

SLC transport function:

The SLC superfamily does not contain active transporters that directly use the energy released by ATP hydrolysis to drive the transport of substances against a concentration gradient. Instead, these proteins act as passive facilitative transporters or secondary active transporters. They facilitate the passive diffusion of specific small molecules, act as exchangers, or utilize ion gradients to drive flow against the gradient. Transmembrane transport is primarily categorized into four types: cotransporters, exchangers, facilitated transporters, and orphan transporters.

（Data source: Matthias A. H, et al. Pflugers Arch. 2004）

SLC transport specificity:

SLC proteins also exhibit a range of substrate specificities. Some proteins can transport a wide range of biomolecules, while others are currently known to transport only a single biomolecule. Still others are "orphan" transporters—those with no known substrates. Recent assessments estimate that up to 30% of SLC proteins remain orphan transporters. Recent technological developments have provided new approaches to studying these transporters (a. Cellular substrate uptake assays using radioactivity or fluorescence detection; b. Downstream functional assays based on pH and membrane potential measurements; c . Ligand binding assays using detection methods such as radioactivity, fluorescence, mass spectrometry, or thermal shift; d . Phenotypic screening assays using various target identification methods).

(Data source: Wang WW, et al. J Med Chem. 2020)

SLC Structure & Modification:

Because SLCs are grouped together as a "superfamily," SLC proteins belonging to different SLC families possess a variety of distinct three-dimensional folds that are not all phylogenetically related. Despite this, most SLC transporters share certain common structural features: when analyzing hydropathic maps, SLC proteins contain between one and 16 transmembrane domains, with the majority (~83%) tending to contain between seven and 12 transmembrane domains. This has led to a persistent problem in studying the structure and function of SLC proteins: the difficulty of expression and purification, and to date, few high-resolution structures of human SLC proteins have been determined. 

（Data source: Custódio TF, et al. Life Sci Alliance. 2021）

At the same time, SLC proteins are regulated by different post-translational modifications of the intracellular loops between the transmembrane domain and the N and/or C termini: these modifications include phosphorylation, acetylation and ubiquitination, while the extracellular loops and termini can be heavily glycosylated, modifications that have been shown to affect transport rate, affinity for its substrates and protein activity.

（Data source: Mikros E, et al. Open Biol. 2019）

SLC distribution:

SLC transporters are widely present and abundant in the body: they act as barriers in protective organs such as the intestine and placenta, and are also ubiquitous in major metabolic organs. In addition to different tissues, different organelles are also crucial for SLCs. For example, the SLC30A family mediates zinc transport in the nucleus (SLC30A9), endosomes (SLC30A4), Golgi apparatus (SLC30A5, SLC30A6, SLC30A7), and secretory granules of alkaline phosphatase (ALP) (SLC30A8).

（Data source: Zhang Y, et al. J Mol Cell Biol. 2019）

SLC and diseases:

The brain and kidneys are target organs for diseases mediated by SLC proteins, with high expression levels. Current SLC drug development is promising for neural and metabolic targets. Previously approved drugs are widely used to treat hyperglycemia, diuresis, movement disorders, urination, gout, and other conditions. Newly tested SLC drugs have the potential to exert anti-tumor effects, improve type 1 diabetes, combat constipation, and prevent hypertension and schizophrenia.

（Data source: Zhang Y, et al. J Mol Cell Biol. 2019）

At the same time, research on the strong association between SLC proteins and various diseases is becoming more and more in-depth, such as:

SLC4A4 inhibition in cancer cells from patients with pancreatic ductal adenocarcinoma (PDAC) alleviates the acidic tumor microenvironment (TME) acidosis caused by bicarbonate accumulation in the extracellular space and reduces lactate production by cancer cells due to reduced glycolysis. SLC4A4 targeting improves T cell-mediated immune responses and disrupts macrophage-mediated immunosuppression, thereby inhibiting tumor growth and metastasis. Furthermore, SLC4A4 targeting combined with immune checkpoint blockade can overcome immunotherapy resistance and prolong survival.

（Data source: Cappellesso F, et al. Nat Cancer. 2022）

Pharmacological or genetic blockade of the PPARA-SLC47A1 pathway augmented the anticancer activity of ferroptosis inducers in mice, establishing a direct molecular link between ferroptosis and lipid transporters, which may provide metabolic targets for overcoming drug resistance.

（Data source: Lin Z, et al. Nat Commun. 2022）

Conclusion

As the largest family of transporters, SLC membrane transporters are not fully utilized in pharmacology compared to other protein families, and many available chemical tools have suboptimal selectivity and efficacy. However, this does not affect the pharmaceutical industry 's favor and attention to them: Jnana Therapeutics Inc. is the first medical company focused on SLC transporters. The company's goal is to explore the mechanisms of SLC-related immune metabolism, lysosomal function, and mucosal defense, and to develop drugs for immuno-oncology, inflammatory diseases, and neurological diseases. Its first pipeline is a small molecule inhibitor of SLC6A19, which is responsible for the reabsorption of phenylalanine back into the bloodstream by the kidneys, providing a promising new approach to reducing plasma phenylalanine levels. Phase I clinical trials are currently underway.