ITPKA promotes invasive phenotypes in clear cell renal cell carcinoma through functional modulation of PPAR signaling

Inositol-trisphosphate 3-kinase A (ITPKA) has been implicated in tumor progression; however, its potential role in clear cell renal cell carcinoma (ccRCC) remains insufficiently defined. This study investigated the expression pattern, prognostic relevance, and potential functional associations of ITPKA in ccRCC. Bioinformatic analyses were performed using TCGA and GEPIA2 datasets to evaluate ITPKA expression, clinicopathological relevance, survival associations, immune infiltration patterns, and enriched signaling pathways. Immunohistochemical (IHC) staining was conducted in 20 paired ccRCC and adjacent non-tumor tissue samples to provide exploratory protein-level validation. Functional assays were performed in 786-O cells following ITPKA knockdown or overexpression. Rescue assays targeting PPAR pathway, using the PPARγ antagonist GW9662 and PPARG overexpression, were used to examine whether PPAR signaling mediates ITPKA-associated cellular phenotypes. ITPKA expression was upregulated in ccRCC tissues and associated with adverse clinicopathological characteristics and unfavorable survival outcomes in the TCGA-KIRC cohort. Exploratory IHC analysis confirmed stronger ITPKA staining in ccRCC tissues than in matched adjacent normal tissues. Immune infiltration analysis suggested a possible association between ITPKA expression and specific immune cell populations, particularly Treg and Th2 cells. In 786-O cells, ITPKA knockdown attenuated malignant cellular phenotypes, including migration and invasion. Rescue assays showed that PPARγ inhibition with GW9662 partially reversed the effects of ITPKA knockdown, whereas PPARG overexpression attenuated the phenotypic changes induced by ITPKA overexpression. However, the present study does not establish a direct biochemical interaction between ITPKA and PPAR pathway components. In conclusion, ITPKA may serve as a potential biomarker and functional regulator in ccRCC. These findings provide preliminary evidence for an ITPKA-PPAR-related regulatory axis and warrant further validation in larger clinical cohorts and additional experimental models.