Transmembrane protein TMEM98 as a multifunctional regulator in cancer: from signaling pathways to translational implications.

Transmembrane (TMEM) protein family members increasingly feature as clinically actionable regulators of cellular physiology and pathology, most notably in cancer biology. Several family members (e.g., TMEM16A/ANO1) have already progressed into first‑in‑human trials or pre‑market diagnostic kits, underscoring the druggability of the TMEM class. Among them, TMEM98 is a multifaceted protein implicated in pivotal processes like cell growth, migration, adhesion, and intracellular signaling. TMEM98 has recently been shown to be involved in major oncogenic pathways like Wnt/β-catenin and AKT/GSK3β, and interacts with transcription factors like MYRF and NF90. Clinically, aberrant TMEM98 expression (e.g., high expression detected in 67.8% of hepatocellular carcinoma specimens, which was associated with early tumor recurrence and poorer overall and disease-free survival) correlates significantly with prognosis, tumor aggressiveness, chemoresistance, and responsiveness to therapy, making it a promising candidate for biomarker-driven personalized oncology. Such findings highlight TMEM98's role in tumor initiation as well as tumor progression. This review integrates current information on TMEM98's functional roles in various malignancies, ranging from lung, gastric, hepatic, ovarian, to head and neck cancer. We further discuss implications of TMEM98 gene mutations, its regulation by non-coding RNA, and its prospective role as a marker and therapeutic target within the translational pipeline. By correlating outcomes of functional assays and clinical cohorts, our goal is to reveal the TMEM98-centered regulation landscape and identify its oncological relevance.