PAR1 inhibition sensitizes HPV-negative HNSCC cells to ferroptosis through inhibition of the STAT3-mediated regulation of iron and lipid metabolic pathways.

Abstract

Ferroptosis, a cell death mechanism characterized by the accumulation of lipid peroxides and subsequent membrane disruption, is emerging as a promising strategy for cancer treatment. However, many tumors, including head and neck squamous cell carcinoma (HNSCC), show resistance to ferroptosis, which reduces its therapeutic effect. Protease-activated receptors (PARs) are highly expressed in many tumors and are closely associated with tumor progression. Our study showed that the expression of protease-activated receptor 1 (PAR1) was downregulated during ferroptosis in HPV-negative HNSCC. Further studies showed that downregulation of PAR1 expression could enhance the therapeutic effect of Erastin on HPV-negative HNSCC, where PAR1 regulated the expression levels of SLC7A11, GPX4, and FTH1. In addition, we found that PAR1 activated the JAK2/STAT3 pathway in a Rac-1-dependent manner and identified STAT3 as a critical transcription factor in PAR1-mediated HPV-negative HNSCC progression and ferroptosis regulation. Inhibition of STAT3 expression attenuated the tumorigenicity of PAR1. It is worth noting that the PAR1 small molecule inhibitor Vorapaxar can further enhance the therapeutic effect of Erastin on HPV-negative HNSCC. Therefore, we propose that PAR1 participates in the progression of HPV-negative HNSCC through STAT3 and reduces the sensitivity of HPV-negative HNSCC to ferroptosis, providing a new perspective for discovering ferroptosis regulatory factors.