The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma

Abstract

Renal cell carcinoma (RCC), a therapeutically recalcitrant genitourinary malignancy, exemplifies the profound interplay between oncogenic signaling and metabolic adaptation. Emerging evidence positions metabolic reprogramming as a central axis of RCC pathogenesis, characterized by dynamic shifts in nutrient utilization that transcend canonical Warburg physiology to encompass lipid anabolism, glutamine auxotrophy, and microenvironment-driven metabolic plasticity. This orchestrated rewiring of cellular energetics sustains tumor proliferation under hypoxia while fostering immunosuppression through metabolite-mediated T cell exhaustion and myeloid-derived suppressor cell activation. Crucially, RCC exhibits metabolic heterogeneity across histological subtypes and intratumoral regions-a feature increasingly recognized as a determinant of therapeutic resistance. Our review systematically deciphers the molecular architecture of RCC metabolism, elucidating how VHL/HIF axis mutations, mTOR pathway dysregulation, and epigenetic modifiers converge to reshape glucose flux, lipid droplet biogenesis, and amino acid catabolism. We present novel insights into spatial metabolic zonation within RCC tumors, where pseudohypoxic niches engage in lactate shuttling and cholesterol efflux to adjacent vasculature, creating pro-angiogenic and immunosuppressive microdomains. Therapeutically, we evaluate first-in-class inhibitors targeting rate-limiting enzymes in de novo lipogenesis and glutamine metabolism, while proposing biomarker-driven strategies to overcome compensatory pathway activation. We highlight the synergy between glutaminase inhibitors and PD-1 blockade in reinvigorating CD8⁺ T cell function, and the role of lipid-loaded cancer-associated fibroblasts in shielding tumors from ferroptosis. Finally, we outline a translational roadmap integrating multi-omics profiling, functional metabolomics, and spatial biology to match metabolic vulnerabilities with precision therapies.

Fig. 1. Glucose metabolism and lipid metabolism reprogramming in RCC.

The balance between gluconeogenesis and glycolysis is intricately regulated during kidney cancer progression. The reciprocal regulatory interaction between FBP1 and EZH2, key components of gluconeogenic pathways, has been identified as a potential therapeutic target for renal cell carcinoma (RCC). In contrast, the glycolysis-associated gene DEPDC1 plays a pivotal role in driving malignant progression and drug resistance in RCC, suggesting that glycolysis inhibitors such as 3BrPA may offer promising targeted therapeutic options for ccRCC. Additionally, PFKFB4 has been shown to mediate resistance to sunitinib by enhancing the pentose phosphate pathway (PPP). Meanwhile, ubiquinone-cytochrome c reductase hinge protein (UQCRH) and circFOXP1 influence RCC progression through their impact on the Warburg effect. RCC progression is significantly influenced by key enzymes involved in the fatty acid metabolic pathway. Malonyl coenzyme A decarboxylase (MLYCD) and E3 ubiquitin ligase TRIM21 suppress tumor progression by inhibiting fatty acid synthesis and promoting fatty acid oxidation. Conversely, the AMPK-GATA3-ECHS1 pathway facilitates fatty acid synthesis and supports cancer cell proliferation. Additionally, hypoxia-inducible factors (HIFs) inhibit fatty acid oxidation by downregulating carnitine palmitoyltransferase 1 (CPT1). Created by Biorender.com. RCC renal cell carcinoma, UQCRH ubiquinone-cytochrome c reductase hinge protein, PPP pentose phosphate pathway, MLYCD malonyl coenzyme A decarboxylase, HIFs hypoxia-inducible factors, CPT1 carnitine palmitoyltransferase 1.

Fig. 2. Amino acid metabolism reprogramming in RCC.

Glutamine metabolism plays a pivotal role in the metabolic reprogramming of renal cell carcinoma (RCC). The aminotransferase inhibitor JHU-083 has been shown to significantly suppress tumor growth, while the glutaminase (GLS) inhibitor CB-839 similarly demonstrated a marked ability to inhibit the growth of xenograft tumors. Created by Biorender.com. RCC renal cell carcinoma, GLS glutaminase, GSH glutathione, GSSG glutathione disulfide, ALT Alanine aminotransferase, AST Aspartate aminotransferase, GST glutathione S-transferase, GPX Glutathione peroxide.