PRDX4 attenuates mitochondrial dysfunction by targeting CALR/SERCA2 interaction to suppress mitochondrial apoptosis in laryngeal squamous cell carcinoma.

Cancer cells exploit antioxidant defense systems to counteract oxidative stress, thereby facilitating proliferation and metastatic dissemination. Peroxiredoxins (PRDXs) represent a major antioxidant family frequently upregulated in malignancies. Peroxiredoxin 4 (PRDX4) has been implicated in tumor progression; however, its functional role and molecular mechanism in laryngeal squamous cell carcinoma (LSCC) remain largely elusive. In this study, we generated LSCC cell lines with PRDX4 knockdown or overexpression via lentiviral transduction, and subsequently performed prognostic evaluation, RNA sequencing, and systematic assessment of mitochondrial apoptosis, mitochondrial morphology and function, and oxidative stress to characterize the biological functions of PRDX4. In vivo, a subcutaneous xenograft mouse model was established to further validate its tumorigenic effects. Notably, high PRDX4 expression predicted an unfavorable prognosis in LSCC patients. Mechanistically, PRDX4 promoted LSCC progression through upregulation of sarco/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2). Specifically, PRDX4 bound to calreticulin (CALR), thereby disrupting CALR-SERCA2 interaction and leading to increased SERCA2 expression. Consequently, PRDX4-mediated SERCA2 upregulation mitigated mitochondrial calcium overload and suppressed mitochondria-dependent apoptosis, ultimately driving LSCC progression. Collectively, these findings elucidate a key mechanistic axis through which PRDX4 promotes the progression of laryngeal squamous cell carcinoma, highlighting its potential as a prognostic biomarker and therapeutic target.