SRY-related HMG-box 5 enhances chemosensitivity in esophageal squamous cell carcinoma through toll-like receptor 4/NOD-like receptor family pyrin domain containing 3-mediated pyroptosis.

Despite established roles in multiple cancers, the specific function and molecular mechanism of SRY-related HMG-box 5 (SOX5) remain elusive in esophageal squamous cell carcinoma (ESCC). SOX5 expression in ESCC tissues, its correlation with prognosis, and its relationship with toll-like receptor 4 (TLR4) and NOD-like receptor family pyrin domain containing 3 (NLRP3) were assessed with bioinformatic methods. Expression of SOX5 and TLR4 in ESCC cells was detected by quantitative reverse transcription polymerase chain reaction. In SOX5-overexpressing or TLR4-knockdown ESCC cells, cell death was evaluated by propidium iodide staining, migration and invasion were detected using Transwell assays, cell proliferation was assessed by colony formation assay, pyroptosis was observed using an optical microscope and confirmed using Annexin V/7-aminoactinomycin D staining, the binding of SOX5 to the TLR4 promoter was confirmed by chromatin immunoprecipitation assay, and the expression of key pyroptosis pathway proteins (Gasdermin D, Gasdermin D-N, cleaved Caspase-1 (c-CASP1), and NLRP3) was analyzed by Western blot. SOX5 downregulation in ESCC tissues and cells was observed and correlated with shorter survival in patients with ESCC. 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 observed 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. SIGNIFICANCE STATEMENT: SRY-related HMG-box 5 function in esophageal squamous cell carcinoma was uncovered. SRY-related HMG-box 5 regulated toll-like receptor 4/NOD-like receptor family pyrin domain containing 3 to mediate pyroptosis.