TSC22D4 drives clear cell renal cell carcinoma progression and therapy resistance by stabilizing NRF2 through KEAP1 disruption.

Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is highly aggressive and difficult to manage due to its intrinsic resistance to oxidative stress. Nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of oxidative stress responses, is frequently overexpressed in ccRCC and is associated with poor prognosis. NRF2 promotes tumor progression by driving proliferation, metabolic reprogramming, and ferroptosis resistance; however, the upstream mechanisms controlling NRF2 stability remain incompletely understood. Here, we identify TSC22 domain family member 4 (TSC22D4) as a Kelch-like ECH-associated protein 1 (KEAP1)-interacting protein that directly binds to KEAP1 via a conserved ETGE motif. This interaction disrupts the KEAP1-NRF2 complex, preventing NRF2 ubiquitination and degradation, thereby enhancing NRF2 stability and activating antioxidant response element (ARE)-driven transcription. Notably, TSC22D4 upregulates solute carrier family 7 member 11 (SLC7A11), thereby suppressing ferroptosis and conferring resistance to sorafenib in ccRCC. TSC22D4 is markedly overexpressed in ccRCC and promotes tumor cell proliferation, invasion, and metastasis. Clinically, elevated TSC22D4 expression correlates with advanced disease stage and poor patient survival. In conclusion, TSC22D4 promotes ccRCC progression and sorafenib resistance by activating the KEAP1-NRF2-SLC7A11 axis and suppressing ferroptosis, highlighting TSC22D4 as a potential therapeutic target in ccRCC.