Clear cell renal cell carcinoma (ccRCC) is driven by von Hippel-Lindau (VHL) tumor suppressor loss and persistent activation of hypoxia-inducible factors (HIFs), which coordinately regulate angiogenesis, metabolic reprogramming, redox balance, and tumor-immune interactions. Although immune checkpoint inhibitors and vascular endothelial growth factor-targeted therapies have improved outcomes, resistance remains common due to adaptive network plasticity. Selected natural products have been reported to exhibit multitarget regulatory activities that may influence interconnected oncogenic pathways. This review highlights how compounds such as curcumin, resveratrol, quercetin, and epigallocatechin-3-gallate modulate the VHL-HIF axis, disrupt metabolic and redox homeostasis, and influence tumor-immune system interactions in ccRCC. We propose a system-level framework in which natural products enhance therapeutic sensitivity; however, further validation is required for clinical translation.
International journal of molecular sciences. 2026 May 20*** epublish ***
Yao-Chou Tsai, Chung-Che Tsai, Vincent F S Tsai, Chih-Hung Lin, Chan-Yen Kuo
Division of Urology, Department of Surgery, Taipei Tzuchi Hospital, The Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan., Department of Nursing, Cardinal Tien College of Healthcare and Management, New Taipei City 231038, Taiwan., Department of Internal Medicine, Cathay General Hospital, Taipei 106438, Taiwan., Institute of Oral Medicine and Materials, College of Medicine, Tzu Chi University, Hualien 97004, Taiwan.