Kiarash Soltani, pourya kanani, S. Adeleh Razavi, Mehdi Hedayati
Sam68, a member of the signal transduction and activation of RNA (STAR) family, is a multifunctional RNA-binding protein involved in several signaling pathways implicated in cancer development and progression. Although direct evidence linking Sam68 to thyroid cancer remains limited, its involvement in pathways known to contribute to thyroid carcinogenesis suggests a potential role in this disease. This systematic review aimed to synthesize the available evidence regarding the interactions of Sam68 with signaling pathways relevant to thyroid cancer. A systematic literature search was conducted in PubMed, Scopus, and Web of Science from database inception to 26 November 2025 following PRISMA guidelines. Study quality was assessed using the Quality Assessment Tool for In Vitro Studies (QUIN) for in vitro studies and the SYRCLE Risk of Bias tool for animal studies. Thirty-five studies met the eligibility criteria and were included in the review. Current evidence indicates that Sam68 directly interacts with and is phosphorylated by Src-related kinases and modulates several signaling pathways implicated in thyroid carcinogenesis, including RET, PI3K/AKT, MAPK/ERK, Wnt/β-catenin, and JAK/STAT pathways. Sam68 promotes PI3K/AKT signaling through interactions with p85 and regulation of the AKT/FOXO axis, enhances Wnt/β-catenin signaling by facilitating β-catenin nuclear accumulation, and participates in RET-mediated oncogenic signaling. Although these findings are primarily derived from non-thyroid experimental models, they support a biologically plausible role for Sam68 in thyroid cancer biology. This review summarizes the available evidence linking Sam68 to signaling pathways implicated in thyroid carcinogenesis and discusses its potential role in thyroid cancer biology. Although current evidence supports a biologically plausible association, further thyroid-specific experimental and clinical studies are required to determine whether Sam68 has diagnostic, prognostic, or therapeutic relevance in thyroid cancer.