An Atlas of Specificity Protein 1 in Oral Cancer: Networks, Therapeutics, and Priorities: A Scoping Review and scRNA-seq Analysis

Oral squamous cell carcinoma (OSCC) remains the most common oral malignancy and has limited targeted therapeutic options. Specificity protein 1 (Sp1), a versatile zinc-finger transcription factor, has emerged as a pivotal regulator of cellular proliferation, apoptosis, epithelial–mesenchymal transition (EMT), and chemoresistance. However, OSCC-specific evidence has not been systematically integrated. This study synthesizes current evidence on Sp1 expression, regulation, downstream targets, and therapeutic interventions in OSCC to map the landscape and identify priorities for translational research. Following PRISMA-ScR guidelines, PubMed, Embase, Scopus, and Web of Science (2002-2025) were searched for original studies of Sp1 in OSCC/tongue SCC. Data on regulatory mechanisms, downstream targets, phenotypic effects, and therapeutic interventions were extracted. Public scRNA-seq data (GSE103322; 5,865 cells from 18 tumors) were analyzed using patient-aware, cell type-stratified Spearman correlation and gene set enrichment analysis to characterize Sp1-associated transcriptional covariation across tumor compartments. Across thirty-eight studies, Sp1 overexpression was reported in association with advanced clinical stage, metastasis, and poor prognosis, though human-tissue evidence was limited to two studies. Upstream regulations involved tumor-suppressive microRNAs, oncogenic non-coding RNAs, and post-translational modifications. Sp1 transcriptionally activated genes linked to EMT, survival, oncogenic signaling, and immune evasion. Multiple natural and synthetic agents suppressed Sp1 and induced apoptosis, with xenograft validation in several reports. Sp1 is reported to regulate multiple oncogenic programs in OSCC, predominantly in preclinical models. Despite strong preclinical evidence, no Sp1-directed therapy has entered clinical testing, underscoring a critical translational gap and the need for biomarker-driven combination strategies.