A false sense of hypoxia: Pro‑tumorigenic VHL‑HIF2α dysregulation in clear cell renal cell carcinoma (Review)

Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma and is characterized by bi‑allelic inactivation of the von Hippel‑Lindau (VHL) tumor suppressor gene. Loss of VHL leads to stabilization of hypoxia‑inducible factor α (HIFα), creating a persistent pseudohypoxic or ‘false sense of hypoxia’ state in which HIF signalling remains active despite adequate oxygen tension. Within this context, HIF2α functions as the dominant oncogenic isoform and drives angiogenesis, metabolic rewiring, tumor microenvironment remodeling and modulation of immune responses. In parallel, epigenetic reprogramming and super‑enhancer‑driven transcriptional programs reinforce ccRCC growth and progression. In this review, these molecular and epigenetic mechanisms were integrated around the VHL‑HIF2α pseudohypoxia framework with particular emphasis on pathological angiogenesis, metabolic reprogramming, tumor heterogeneity and super‑enhancer biology. Furthermore, current therapeutic strategies, including VEGF/VEGFR‑targeted agents, HIF2α inhibitors, mTOR pathway inhibitors and immune checkpoint blockade, were presented, together with mechanisms that limit response durability. Finally, emerging precision‑oncology approaches aimed at resolving intratumor heterogeneity, identifying predictive biomarkers and exploiting tumor‑ and microenvironment‑specific vulnerabilities to overcome therapeutic resistance were discussed.