Feng Cheng, Mingjia Wang, Yizhuo Hou, Yanqin Wu, Wen Zhang, Yuanyuan Zhang
Hepatocellular carcinoma (HCC) carries high global morbidity and mortality, with dismal prognosis due to hidden onset, limited advanced therapies and prevalent drug resistance. SOX4, a conserved transcription factor, maintains hepatic homeostasis physiologically but undergoes abnormal overexpression in HCC via transcriptional, epigenetic and ceRNA modulation. It acts as a pivotal oncogenic driver, facilitating tumor metastasis, metabolic reprogramming, stem cell retention, immune evasion and treatment resistance. Clinically, SOX4 upregulation is tightly associated with advanced tumor stage and unfavorable survival, representing a promising tissue-based candidate biomarker for HCC diagnosis and prognosis. However, its clinical translation is hindered by cohort heterogeneity, insufficient prospective validation, unclear post-translational modification mechanisms, and the inherent undruggability of transcription factors. This review systematically summarizes the regulatory mechanisms, core oncogenic functions and clinical implications of SOX4 in HCC, discusses current research bottlenecks, and provides future perspectives, aiming to support the development of novel diagnostic biomarkers and targeted therapeutic strategies for HCC.