HIF-2α inhibitors in clear cell renal cell carcinoma: a clinical pharmacy perspective on lipid metabolism, therapeutic management, and resistance strategies

Renal cell carcinoma (RCC), and clear cell renal cell carcinoma (ccRCC) in particular, is characterized by perturbed lipid metabolism and constitutive activation of hypoxia-inducible factor-2α (HIF-2α). This mini review specifically focuses on ccRCC, which represents 80% of all RCC cases and is uniquely characterized by VHL loss and HIF-2α activation. As a central transcription factor, HIF-2α not only regulates the growth and metastasis of tumor cells but also alters lipid metabolism by activating multiple signaling pathways, thereby promoting tumor progression. Despite the significant advances in our understanding of RCC pathogenesis, there is an urgent need for new targeted therapies. The advance in the design of selective HIF-2α inhibitors has uncovered a novel therapeutic path for ccRCC by direct inhibition of this central oncogenic driver. This mini review outlines how HIF-2α inhibitors exert antitumor effects through specific molecular mechanisms, particularly how they modulate lipid metabolism and related molecular networks. And, the latest clinical trial information is used to determine the effectiveness, safety, and translational potential of the ccRCC as a precision therapy. By integrating existing mechanistic and clinical evidence, the present article intends to instruct the design of future drugs and the optimization of therapeutic modalities so that it might impact the clinical management of ccRCC in the future.