HIF-2α/TRIB3/PARP1 axis promotes progression by orchestrating DNA repair in clear cell renal cell carcinoma

In clear cell renal cell carcinoma (ccRCC), aberrant accumulation of hypoxia-inducible factor-2α (HIF-2α) due to VHL gene mutation is a central event driving tumorigenesis and progression. Although DNA damage is a hallmark of renal cancer development, it remains unclear whether and how HIF-2α regulates downstream targets to modulate the DNA damage and repair process. Here, we demonstrate that HIF-2α transcriptionally activates TRIB3 expression. Further we found that TRIB3 interacts with PARP1, a key DNA repair protein, and enhances nuclear PARP1 stability by inhibiting its K63-linked polyubiquitination, thereby promoting the DNA repair capacity of ccRCC cells. Both in vitro and in vivo, the HIF-2α inhibitor belzutifan (PT2977) effectively suppressed this signaling axis and reversed the tumor-promoting effects caused by PARP1 overexpression. Collectively, our findings elucidate a critical role for the HIF-2α/TRIB3/PARP1 axis in ccRCC progression, revealing potential therapeutic targets and rational combination strategies for this disease.