PCDHGC3 silencing promotes clear cell renal cell carcinoma metastasis via mTOR/HIF2α activation, lipid metabolism rewiring, and ferroptosis evasion.

Clear cell renal cell carcinoma (ccRCC) remains a major clinical challenge due to its high metastatic potential and limited treatment options. Here, we identified PCDHGC3 as a critical tumor suppressor, whose downregulation drives ccRCC aggressiveness. Through integrated molecular analyses, we demonstrated that PCDHGC3 deficiency promoted proliferation, epithelial-to-mesenchymal transition, and metastatic dissemination in both in vitro and in vivo models. Mechanistically, PCDHGC3 knockdown activated mTOR signaling, leading to aberrant HIF2α stabilization, a well-established oncogenic driver in ccRCC. Upstream of this cascade, PCDHGC3 loss was associated with increased focal adhesion kinase (FAK) activation, providing a context-specific link between membrane signaling and mTOR-HIF2α pathway activation. Pharmacological inhibition of mTOR suppresses HIF2α activity and targeting either pathway partially rescues the hyperproliferative and pro-metastatic phenotype of PCDHGC3-deficient cells. Proteomic analysis further revealed that PCDHGC3 loss reprograms lipid metabolism, particularly by increasing fatty acid synthesis and lipid droplet (LD) formation. We identify PLIN2, a HIF2α-regulated gene, as a key mediator of LD stability in PCDHGC3-knockdown cells. By sequestering lipids into LDs, PLIN2 protects against ferroptosis, an iron-dependent form of cell death triggered by lipid peroxidation. Notably, PLIN2 knockdown increases ferroptotic sensitivity, revealing LD biogenesis as a major survival mechanism in PCDHGC3-deficient ccRCC. Together, these findings establish a PCDHGC3-mTOR-HIF2α-PLIN2 axis that underlines both metastatic behavior and ferroptosis evasion. Clinically, this suggests that combining ferroptosis inducers with mTOR or HIF2α inhibitors-and potentially targeting PLIN2-could provide a multifaceted therapeutic strategy against advanced ccRCC. By elucidating the tumor-suppressive role of PCDHGC3, this study expands our understanding of clustered PCDH biology and offers novel insights for ccRCC management.