The role of RARG in solid tumor progression and therapeutic potential

Retinoic acid receptor gamma (RARG), a crucial member of the retinoic acid receptors (RARs) family, encompasses two distinct isoforms, namely RARγ1 and RARγ2. RARG is organized into five functional domains: A/B, C, D, E and F. Among them, the C region encodes the DNA-binding domain (DBD), which mediates recognition and binding to retinoic acid response elements (RAREs) in DNA, typically as a heterodimer with retinoid X receptors (RXRs). This RAR-RXR dimer mediates the genomic effects of RARG in a ligand-dependent manner. RARG can be directly activated by all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-cisRA). In cancer cells with low endogenous levels of ATRA, RARG has been identified as a potential oncogenic driver. Recent research has increasingly implicated that RARG is involved in the initiation and progression of solid tumors through both genomic and non-genomic mechanisms. RARG regulates gene expression, cell proliferation and differentiation via Wnt/β-catenin, PI3K/AKT, Hippo-Yap, TRAF6-IL-6-STAT3 and other multiple signaling pathways. This review summarizes the structural and functional features of RARG, highlights its emerging roles in solid tumor biology and discusses therapeutic strategies targeting RARG, aiming to inform future cancer treatment approaches.