Sodium-coupled neutral amino acid transporter SNAT2 regulates alveolar epithelial cell metabolism and homeostasis in acute lung injury

Acute Respiratory Distress Syndrome (ARDS) is the most frequent cause of death in intensive care units, yet effective pharmacological treatments are still lacking. Hallmarks of ARDS include dysfunctional alveolar fluid clearance (AFC) and loss of alveolar-capillary barrier function due to alveolar epithelial cell (AEC) death. The Na + -coupled neutral amino acid (AA) transporter, SNAT2 (SLC38 family), transports one AA along with one Na + . We previously showed that SNAT2 expression in AEC promotes AFC via its Na + transport function. We now hypothesize that SNAT2, through its AA transport function, is a central regulator of AEC metabolism and cell fate in acute lung injury (ALI)/ARDS, and could thus represent a novel therapeutic target. Hence, we aim to investigate SNAT2 as AA transporter and its role in regulating AEC metabolism and homeostasis. Analysis of publicly available single cell RNA sequencing (scRNAseq) data showed that SNAT2 is abundantly expressed in human and mouse AEC. In vivo, LPS intranasal administration (5 mg/kg) to wild type (WT) mice increased lung barrier permeability (bronchoalveolar lavage fluid -BALF- protein), neutrophil infiltration and histological injury. These pathologic features were associated with a metabolic shift in lung tissue from tricarboxylic acid (TCA) cycle metabolites to glycolytic metabolites. Interestingly, glutamate (Glu), which derives from glutamine (Gln), was significantly reduced in the lungs of LPS-treated mice. In vitro, SNAT2 inhibition by α-methylaminoisobutyric acid (MeAIB) induced a similar decrease in intracellular Gln levels in human primary AEC. Seahorse assays demonstrated that SNAT2 inhibition causes a metabolic shift towards glycolysis, analogous to our in vivo observations in LPS-treated mice. Furthermore, stimulation of AEC with cytomix (LPS, IFN-γ, TNF-α, IL-1β) downregulated SNAT2 (both mRNA and protein) and induced a similar shift to glycolysis. To evaluate the functional consequences of SNAT2 loss, we performed loss- or gain-of-function experiments using SNAT2 knockdown (KD) or overexpression (OE), and assessed apoptosis, autophagy, and endoplasmic reticulum (ER)-stress markers (ATF4, CHOP) following stimulation with cytomix or medium alone (control). Similar to MeAIB treatment, SNAT2 KD induced excessive autophagy and upregulated ATF4 and CHOP, ultimately increasing apoptosis. These detrimental effects were reversed by SNAT2 OE. Conversely, SNAT2 KD markedly impaired AEC proliferation (Ki67 expression and BrdU incorporation) and migration (scratch assay), while SNAT2 OE restored the proliferative capacity of AEC. In vivo, Slc38a2+/- global heterozygous mice exhibited increased BALF protein content, histological lung injury scores, and expression of ER-stress makers ATF4 and CHOP in lung tissue compared to WT mice. These findings demonstrated that SNAT2 loss during inflammation promotes ER-stress, excessive autophagy, and apoptosis in AEC. As such, SNAT2 loss may contribute relevantly to the pathogenesis of ALI and impair epithelial repair and regeneration. These effects are likely mediated by impaired Gln uptake and dysregulation of AEC metabolism. Therefore, during inflammation, SNAT2 restoration could represent a novel strategy to restrain ALI pathogenesis by ensuring Gln uptake and TCA cycle activity, thereby supporting lung epithelial cell repair and regeneration. This work was supported by DFG funding (KU1218-11/1 and KU 1218/11-2) to Wolfgang Kuebler and by a CSC scholarship to Gefei Li. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.