Cyclin D1 and the resistance landscape of HIF2 inhibition in clear-cell renal cell carcinoma: Insights from a mini-review.

Clear-cell renal cell carcinoma (ccRCC) is primarily driven by VHL inactivation and subsequent stabilization of hypoxia-inducible factor 2α (HIF2α). The recent approval of the HIF2 inhibitor belzutifan represents a landmark advance, yet both primary and acquired resistance remain major barriers. In this mini-review, we summarize emerging insights into the molecular basis of HIF2 inhibitor response and resistance, with a particular focus on Cyclin D1 as a key downstream effector linking HIF2 signaling to cell-cycle progression. Persistent Cyclin D1 expression, as well as functional compensation by Cyclin D2, underlies diverse resistance phenotypes. Furthermore, the dual contribution of Cyclin D1-driven proliferation and VEGF-mediated angiogenesis explains why durable responses require combined suppression of intracellular and microenvironmental pathways. We also discuss translational opportunities, including HIF2 inhibitor combinations with CDK4/6 inhibitors and anti-VEGF agents, and highlight CCND1/CCND2 as potential biomarkers. Finally, we outline future challenges and perspectives for precision-based, mechanism-driven therapy in ccRCC.