GABPA inhibits tumorigenesis in clear cell renal cell carcinoma by regulating ferroptosis through ACSL4

Clear cell renal cell carcinoma (ccRCC) is a common genitourinary malignancy characterized by dysregulated cellular metabolism leading to aberrant glucose metabolism, fatty acid accumulation, and excessive reactive oxygen species production. ccRCC cells exhibit an augmented oxidative stress response. Complex interactions between iron metabolism and lipid homeostasis in ccRCC cells require a counteracting response that enables ferroptosis evasion and survival maintenance. Additionally, abnormal GA-binding protein transcription factor subunit alpha (GABPA) expression is associated with ccRCC occurrence and development, but its impact on ferroptosis-related molecular mechanisms remains unclear. Herein, we examined the impact of the GABPA-ACSL4 pathway on ferroptosis in ccRCC through bioinformatics analysis, as well as in vitro and in vivo experiments. In contrast to that in adjacent normal tissues, GABPA expression was significantly downregulated in ccRCC tissues, and this downregulation was linked to poor overall survival. Increased GABPA expression suppressed ccRCC cell proliferation, migration, and invasion. Moreover, GABPA overexpression increased the susceptibility of ccRCC cells to ferroptosis. Additionally, GABPA directly bound to the promoter region of ACSL4, promoting ferroptosis. Thus, inducing the GABPA-ACSL4 pathway activates ferroptosis, inhibits proliferation or metastasis, and exerts anticancer activity in ccRCC. These findings have important implications for regulating ccRCC occurrence and development.