IGFBP1 orchestrates metabolic reprogramming to drive clear cell renal cell carcinoma progression through NR1H4-mediated lipid homeostasis disruption

The hallmark lipid accumulation phenotype observed in clear cell renal cell carcinoma (ccRCC) serves as a critical pathophysiological driver of tumor progression. Our investigation revealed that IGFBP1 expression was significantly elevated in ccRCC versus matched normal renal tissues, with increased levels correlating with poorer patient survival outcomes. IGFBP1 knockdown not only suppressed tumor proliferation and invasiveness in vitro but also provoked substantial lipidomic remodeling, as validated through comprehensive lipidomic profiling. Specifically, IGFBP1-deficient cells demonstrated marked reductions in triglycerides (TGs), diacylglycerols (DAGs), free fatty acids (FFA), and cholesterol esters (CEs), thereby establishing IGFBP1 as a key regulator of the metabolic derangements' characteristic of ccRCC pathogenesis. Mechanistic exploration identified NR1H4 as a potential transcriptional regulator operating downstream of IGFBP1-mediated signaling pathways. A thorough interrogation of these pathways established mechanistic links between IGFBP1 activity and endoplasmic reticulum stress, revealing an integrated network that coordinates lipid homeostasis within malignant renal epithelium. These findings substantiated the role of IGFBP1 as a central node in the metabolic reprogramming associated with ccRCC and propose actionable targets for therapeutic intervention through modulation of lipid metabolic pathways.