Background: In head and neck squamous cell carcinoma (HNSCC), solute carrier family 16 member 1 (SLC16A1) is associated with tumor advancement and reduced sensitivity to ferroptosis, yet the molecular basis of these effects remains unclear. This study seeks to uncover how SLC16A1 contributes to HNSCC tumorigenesis. Methods: To elucidate how SLC16A1 drives HNSCC progression via ferroptosis resistance, we performed RNA sequencing on SLC16A1-knockdown HNSCC cells and controls, followed by functional validation. We next systematically assessed the role of the candidate molecule solute carrier family 7 member 11 (SLC7A11) in HNSCC progression and resistance to ferroptosis using loss- and gain-of-function experiments in vitro and xenograft-based assays in vivo. Finally, we applied RNA interference and validated expression changes by quantitative real-time polymerase chain reaction and immunoblotting to map the signaling pathway by which SLC16A1 controls SLC7A11 expression. Results: Integrated RNA sequencing and functional assays identified SLC7A11 as a key downstream effector of SLC16A1. SLC7A11 mediates SLC16A1-driven tumor cell proliferation, ferroptosis resistance, and tumorigenesis. Mechanistically, SLC16A1 activates signal transducer and activator of transcription 3 (STAT3) to transcriptionally upregulate SLC7A11 expression. Conclusion: Our study defines a novel SLC16A1–STAT3–SLC7A11 signaling axis that promotes HNSCC progression by conferring robust resistance to ferroptosis. This axis may be leveraged as a therapeutic target to mitigate treatment resistance.
Tian et al. (Thu,) studied this question.