O-GlcNAcylation of DJ-1 suppresses ferroptosis in renal cell carcinoma by affecting the transsulfuration pathway

Renal cell carcinoma (RCC) is one of the most common urological malignancies worldwide, and advanced patients often face challenges with chemotherapy resistance and poor prognosis. Ferroptosis, a novel form of cell death, offers potential therapeutic prospects. In this study, we found that DJ-1 was elevated in kidney renal clear cell carcinoma (KIRC), and this abnormal expression pattern was closely associated with clinical pathological characteristics and worse prognosis. Our experiments both in vivo and in vitro revealed that DJ-1 enhanced the malignant characteristics of KIRC, leading to increased tumor growth. Additionally, DJ-1 inhibited ferroptosis through promoting homocysteine (Hcy) synthesis in the transsulfuration pathway in KIRC cells. Mechanistic studies revealed that O-GlcNAc transferase (OGT) mediated O-GlcNAcylation of DJ-1 was crucial for maintaining its homodimeric structure. Importantly, O-GlcNAcylation-deficient mutation of DJ-1 at T19 residue enhanced the interaction between S-adenosyl homocysteine hydrolase (SAHH) and the negative regulatory factor S-adenosyl homocysteine hydrolase-like-1 (AHCYL1), thereby inhibited the activities of SAHH and transsulfuration pathway. In summary, the oncogenic role of DJ-1 in KIRC was closely related to the reduction of ferroptosis, and the O-GlcNAcylation of DJ-1 exerted an antioxidant effect by activating the transsulfuration pathway. Therefore, DJ-1, specifically O-GlcNAcylation of DJ-1 could represent an important target for ferroptosis-based anti-tumor therapy.