MT1G promotes the progression of ccRCC by suppressing ferroptosis through activation of the PI3K–AKT pathway

Clear cell renal cell carcinoma (ccRCC) is the most common and clinically aggressive malignancy of the urinary system, characterized by dysregulated signaling pathways and resistance to ferroptosis. Metallothionein-1 G (MT1G) is generally downregulated in ccRCC; however, its elevated expression is paradoxically associated with poor prognosis, suggesting a pro-tumorigenic role. In this study, we integrated bioinformatics analyses with in vitro and in vivo experiments to investigate the biological function and underlying mechanisms of MT1G in ccRCC. Our results show that although MT1G is globally downregulated in ccRCC tissues, its expression positively correlates with PI3K-AKT pathway activity and ferroptosis suppression. Functional experiments revealed that MT1G knockdown inhibits proliferation, clonogenicity, and migration, while promoting ferroptosis and reducing PI3K-AKT activity. Conversely, MT1G overexpression or treatment with the PI3K agonist UCL-TRO-1938 rescues these phenotypes. In vivo xenograft models confirmed that MT1G silencing suppresses tumor growth, accompanied by reduced PI3K-AKT activity and downregulation of ferroptosis-suppressive markers, effects reversible by UCL-TRO-1938. Collectively, these findings demonstrate that MT1G promotes ccRCC progression by activating the PI3K-AKT pathway and suppressing ferroptosis, providing a mechanistic basis for its prognostic significance and potential as a therapeutic target.