Background <p><?tk 2?>Oral cancer is the most common malignancy of the oral cavity and facial region, affecting the mucosal and epithelial surfaces in the mouth and lips. Unfortunately, OC is often associated with a high mortality rate and limited treatment options for patients.<?tk 0?></p> Methods and results <p><?tk 2?>Herein, we used in silico analysis and in vitro assays to investigate the impact of the Sigma-1 receptor (SIGMAR1) in OC progression by evaluating mitochondrial function, calcium signaling and clonogenic growth. First, the data from the TCGA pan-cancer analysis revealed that SIGMAR1 was overexpressed in OC versus healthy tissue and related to a worse survival rate. Furthermore, we demonstrated that SIGMAR1 silencing led to an increase in mitochondrial membrane potential, a reduction in cellular ATP levels, inhibition of Ca²⁺ influx, and a significant decrease in the clonogenic growth of OC cells.<?tk 0?></p> Conclusions <p><?tk 2?>Based on these findings, we suggest that SIGMAR1 may influence mitochondrial membrane potential and energy production by modulating Ca²⁺ uptake, which is critically important to cellular survival. In addition, SIGMAR1 knockdown may offer a potential strategy to be further explored as treatment for OC.<?tk 0?></p> Graphical abstract <p></p>