SOX5 Enhances Chemosensitivity in Esophageal Squamous Cell Carcinoma Through TLR4/NLRP3-Mediated Pyroptosis

Despite established roles in multiple cancers, the specific function and molecular mechanism of SOX5 remain elusive in esophageal squamous cell carcinoma (ESCC). SOX5 expression in ESCC tissues, its correlation with prognosis, and its relationship with TLR4 and NLRP3 were assessed with bioinformatic methods. Expression of SOX5 and TLR4 in ESCC cells was detected by RT-qPCR. In SOX5-overexpressing or TLR4-knocking down ESCC cells, cell death was evaluated by PI staining; migration and invasion were detected using Transwell assays; cell proliferation was assessed by colony formation assay; pyroptosis was observed using optical microscope and confirmed using Annexin V/7-AAD staining; the binding of SOX5 to the TLR4 promoter was confirmed by ChIP assay; and the expression of key pyroptosis pathway proteins (GSDMD, GSDMD-N, c-CASP1, NLRP3) were analyzed by Western blot. SOX5 downregulation in ESCC tissues and cells was observed and correlated with shorter survival in ESCC patients. SOX5 expression positively correlated with the key pyroptosis pathway genes TLR4 and NLRP3. SOX5 overexpression promoted ESCC cell pyroptosis and enhanced sensitivity to cisplatin (DDP). Mechanistically, SOX5 interacted with the TLR4 promoter and upregulated key pyroptosis pathway proteins; TLR4 knockdown reduced the enhanced pyroptosis and DDP sensitivity in SOX5-overexpressing cells. SOX5 enhances DDP sensitivity in ESCC by mediating TLR4/NLRP3 expression to promote cell pyroptosis, providing novel insights for ESCC treatment.