Adaptively increased intake of arginine sustains oral keratinocyte survival through alleviating oxidative stress during targeting glutamine metabolism.

Abstract

Glutamine is a crucial amino acid with a variety of important roles in both health and disease, with ASCT2 (alanine-serine-cysteine transporter 2)-mediated uptake being critical for cellular homeostasis. While ASCT2 inhibition has been proposed as a therapeutic strategy for oral malignancies, our prior work revealed its paradoxical pro-tumorigenic effects in oral squamous cell carcinoma (OSCC), underscoring the complexity of glutamine metabolism targeting. Here, we identify a compensatory arginine-dependent survival mechanism in oral epithelial cells under glutamine restriction. ASCT2-knockout mice exhibit homeostasis in proliferation and apoptosis through SLC7A2 (solute carrier family 7 member 2) upregulation, a process driven by ROS/NF-κB signaling. Increased intracellular arginine serves as an effector for mTOR/S6 activation to promote cell growth in response to glutamine restriction. Additionally, arginine uptake could effectively alleviate oxidative stress and reduce cell apoptosis via the synthesis of glutathione (GSH) and the activation of NRF2/HO-1 signaling upon ASCT2 knockdown. These results not only delineate the metabolic reprogramming cascade mediated through ASCT2 suppression, but more importantly, reveal a clinically actionable strategy of dual glutamine-arginine metabolic intervention with translational promise for overcoming therapy resistance across multiple pathological states, particularly in malignancies exhibiting metabolic plasticity.