Metabolic Hub, Reprogramming Disease: SLC3A2 – From Amino Acid Transport Mechanism to Emerging Therapeutic Target

1. Why Is SLC3A2 a Central Hub in Metabolism and Disease?

2. How Does SLC3A2 Execute Its Key Biological Functions?

3. How Does SLC3A2 Regulate Critical Cellular Signaling Pathways?

4. In Which Major Diseases Does SLC3A2 Play a Key Role?

5. What Is the Progress in Developing Drugs Targeting SLC3A2?

1. Why Is SLC3A2 a Central Hub in Metabolism and Disease?

SLC3A2 (Solute Carrier Family 3 Member 2, also known as 4F2hc or CD98hc) is a type II transmembrane glycoprotein belonging to the SLC3 family. Its primary function is to form heterodimeric amino acid transporters (HATs) with light chain subunits from the SLC7 family, jointly mediating the transmembrane transport of amino acids and regulating cellular metabolism and signaling activities ^[1,2].

SLC3A2 consists of a short N-terminal cytoplasmic region, a single transmembrane helix (TM), and a large C-terminal extracellular domain (ED). Although structurally similar to bacterial glucosidases, the extracellular domain lacks catalytic activity and primarily functions in protein-protein interactions and conformational stabilization ^[1]. Via conserved disulfide bonds, SLC3A2 forms complexes with SLC7 family members (such as LAT1, xCT, etc.) to fulfill its transport function. In this heterodimer, SLC3A2 is responsible for trafficking the light chain subunits to the plasma membrane and maintaining their stability, while substrate recognition and ion selectivity are determined by the light chain subunits ^[2,3].

SLC3A2 is highly expressed in various tissues with high metabolic rates, including the blood-brain barrier (BBB), placenta, and immunologically activated cells ^[4-7]. Its absence during embryonic development is lethal, while in tumor cells, SLC3A2 is often significantly upregulated to enhance amino acid supply and promote growth and metabolic reprogramming ^[8,9]. These characteristics establish SLC3A2 as a crucial hub connecting nutrient metabolism and signal regulation.

2. How Does SLC3A2 Execute Its Key Biological Functions?

2.1 Amino Acid Transport Mechanisms

SLC3A2 mediates the transport of various types of amino acids by forming complexes with different light chain subunits:

4F2hc-LAT1 (system L): Sodium-independent transport of large neutral amino acids (e.g., leucine, isoleucine), operating via the "alternating access model" for transmembrane exchange; also transports substrates like L-DOPA and thyroid hormones ^[9,10].
4F2hc-xCT (system xc⁻): Mediates the 1:1 exchange of extracellular cystine and intracellular glutamate, providing cysteine for glutathione (GSH) synthesis and maintaining cellular redox balance ^[9].
4F2hc-LAT2 and 4F2hc-y+LAT1/2 are involved in the reabsorption of small neutral amino acids and the metabolism of cationic amino acids, respectively, playing important roles in the kidneys, intestines, and immune cells ^[11,12].

2.2 N-glycosylation and Localization Regulation

N-glycosylation is a key modification for maintaining SLC3A2 function. In pancreatic cancer, glycosylation at Asn365, catalyzed by B3GNT3, significantly enhances protein stability and xCT binding, thereby sustaining system xc⁻ activity and protecting against ferroptosis ^[9]. Defects in glycosylation accelerate degradation and increase sensitivity to ferroptosis.

SLC3A2 is primarily localized to the plasma membrane but can also be targeted to the lysosomal membrane due to signaling stimuli or protein interactions (e.g., with LAPTM4b or DRAM-1), participating in amino acid storage and mTORC1 signaling regulation ^[10,15].

3. How Does SLC3A2 Regulate Critical Cellular Signaling Pathways?

3.1 mTORC1 Signaling Pathway

SLC3A2-mediated leucine uptake is a key step for activating the mTORC1 signaling pathway. Leucine regulates Rag GTPase activity through the Sestrin-GATOR and LRS pathways, promoting mTORC1 activation on the lysosomal membrane, thereby stimulating protein synthesis and cell growth [16,17]. In head and neck squamous cell carcinoma, loss of SLC3A2 reduces mTORC1 activity and triggers autophagy, while inhibition of autophagy enhances radiosensitivity ^[3].

3.2 Integrated Stress Response (ISR)

When SLC3A2 function is impaired, amino acid depletion leads to the accumulation of uncharged tRNA, activating the GCN2–eIF2α–ATF4 pathway. ATF4, in turn, promotes the expression of SLC3A2 and LAT1, restoring amino acid homeostasis ^[19]. This mechanism is particularly prominent in high-metabolism tumors such as prostate cancer.

3.3 Integrin Signaling Pathway

The intracellular domain of SLC3A2 can interact with integrin β subunits, influencing cell adhesion and migration ^[2,20]. In liver cancer, SLC3A2 can inhibit β1 integrin activation to restrict invasion; whereas in renal cancer, it promotes integrin signaling, enhancing migration and matrix adhesion capabilities ^[20].

4. In Which Major Diseases Does SLC3A2 Play a Key Role?

As a nodal point linking amino acid metabolism and signaling pathways, SLC3A2 is closely associated with the occurrence and progression of various diseases.

4.1 Cancer

4.1.1 Prostate Cancer

SLC3A2 is a downstream target gene of the androgen receptor splice variant AR-V7. AR-V7 drives its expression and activates mTORC1 signaling via the LAT1 complex, thereby supporting the growth of castration-resistant prostate cancer (CRPC) ^[8,11]. Clinical data show that high SLC3A2 expression is closely correlated with higher pathological grade and poor prognosis ^[21].

4.1.2 Pancreatic Cancer

In pancreatic ductal adenocarcinoma (PDAC), B3GNT3-mediated N-glycosylation enhances SLC3A2 stability and promotes xCT binding, maintaining system xc⁻ function and antioxidant capacity [9]. This mechanism confers significant tolerance to ferroptosis in PDAC cells. Analysis of clinical samples indicates that dual high expression of SLC3A2 and B3GNT3 is closely associated with shortened survival, suggesting their potential as prognostic biomarkers.

4.1.3 Head and Neck Squamous Cell Carcinoma (HNSCC)

High SLC3A2 expression promotes amino acid transport and DNA repair capacity, conferring radioresistance to tumor cells ^[3]. Knockdown of SLC3A2 or inhibition of mTORC1 can attenuate radioresistance, and combined autophagy inhibition further enhances therapeutic efficacy, suggesting its potential as a target for radiosensitization.

4.1.4 Urological Tumors

In bladder cancer and renal cell carcinoma, the SLC3A2–LAT1 complex mediates leucine uptake, promoting cell proliferation and invasion ^[21,22]. High SLC3A2 expression is closely associated with high grade, metastatic risk, and poor prognosis, indicating its potential diagnostic and therapeutic value in urological tumors.

4.1.5 Other Malignancies

In hepatocellular carcinoma, breast cancer, and glioma, SLC3A2 has also been found to regulate the mTORC1 pathway and integrin signaling, thereby influencing cell metabolism, migration, and stress response capacity. These findings support its potential as a dual "metabolism-signaling" target in precision cancer therapy.

4.2 Neurological Diseases

SLC3A2 is highly expressed at the blood-brain barrier (BBB) and is closely involved in maintaining brain amino acid homeostasis. LAT1 gene mutations (Ala246Val, Pro375Leu) impair the function of the SLC3A2-LAT1 complex, leading to brain amino acid imbalance, activation of the ISR pathway, and phenotypes associated with autism spectrum disorder (ASD) ^[22,23]. Furthermore, in Parkinson's disease, the SLC3A2–LAT1 complex is responsible for the brain transport of L-DOPA. Branched-chain amino acids (BCAAs) can competitively bind to it, reducing L-DOPA treatment efficiency, explaining the drug tolerance observed in some patients ^[24].

4.3 Metabolic Diseases

SLC3A2 is closely linked to BCAAs metabolism, insulin resistance, and type 2 diabetes (T2DM). BCAA uptake mediated by the SLC3A2-LAT1 complex can excessively activate mTORC1, thereby inhibiting insulin signaling and inducing insulin resistance ^[25]. Additionally, hyperglycemia can inhibit AMPK signaling and downregulate SLC3A2 expression, further elevating plasma BCAA levels and creating a vicious metabolic cycle ^[25]. In pancreatic β-cells, SLC3A2 participates in amino acid uptake and insulin synthesis; its dysfunction can lead to insufficient secretion and exacerbate metabolic imbalance ^[26].

4.4 Inflammatory and Immune-Related Diseases

SLC3A2 plays a key role in the metabolic reprogramming of immune cells.

During T cell activation, its expression is significantly upregulated, supporting effector T cell differentiation and cytokine secretion by enhancing amino acid supply. Inhibition of SLC3A2 can attenuate T cell activation and alleviate Th2-mediated allergic inflammation ^[27].
In B cells, SLC3A2-mediated leucine uptake activates the mTORC1 pathway, promoting the production of inflammatory factors (IL-6, TNF-α), and shows a positive correlation with disease activity in rheumatoid arthritis ^[28].

These results indicate that SLC3A2 is not only a metabolic channel protein but also participates in the metabolic regulation of immune signals, representing a new potential therapeutic target for inflammatory diseases.

5. What Is the Progress in Developing Drugs Targeting SLC3A2?

SLC3A2 has emerged as a novel anti-cancer drug target. Current research directions cover monoclonal antibodies, small molecule inhibitors, and antibody-drug conjugates (ADCs), primarily focused on hematological malignancies, solid tumors, and brain cancers, all currently in the preclinical stage.

Drug	Mechanism of Action	Drug Type	Indications Under Investigation	Highest R&D Stage
MAb52-4.2	SLC3A2 Modulator	Monoclonal Antibody	Hematological Tumors \| Solid Tumors	Preclinical
211At-TLX-102	SLC3A2 Inhibitor \| SLC7A5 Inhibitor	Small Molecule / Therapeutic Radiopharmaceutical	Brain Cancer	Preclinical
c-SF-25 Mab(Kagoshima University)	SLC3A2 Inhibitor	Monoclonal Antibody	Adult T-cell Leukemia/Lymphoma	Preclinical
NPB15	SLC3A2 Inhibitor	Monoclonal Antibody	Hepatocellular Carcinoma	Preclinical
HH018-sesutecan	SLC3A2 Inhibitor	ADC	Tumors	Preclinical

(Data current as of October 30, 2025, sourced from Synapse)

6. SLC3A2 Research Tools

● SLC3A2 Recombinant Protein

Recombinant Human Amino acid transporter heavy chain SLC3A2 (SLC3A2), partial (Active); CSB-MP021640HU1

● SLC3A2 Antibodies

SLC3A2 Recombinant Monoclonal Antibody

CSB-RA021640MA1HU

SLC3A2 Antibody

CSB-PA021640LA01HU

● SLC3A2 Cell Line

HEK293T/Human SLC7A11 & SLC3A2 Stable Cell Line; CSB-SC5338HU

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