The long isoform of FABP6 facilitates WWP2-mediated PTEN ubiquitination to activate AKT/mTOR signalling and contributes to reduced everolimus sensitivity in clear cell renal cell carcinoma

How PTEN function is impaired in clear cell renal cell carcinoma (ccRCC) without detectable genomic alterations remains unresolved. We investigated whether the long isoform of fatty acid-binding protein 6 (FABP6L) contributes to this process. Analyses that distinguished FABP6 isoforms identified FABP6L as the principal tumour-upregulated variant, whereas the short isoform, FABP6S, did not show a comparable increase. SHOX2 depletion preferentially reduced FABP6L expression. Biochemical experiments linked FABP6L to increased association between PTEN and the E3 ligase WWP2, enhanced PTEN polyubiquitination, and reduced PTEN protein stability. These changes were accompanied by increased AKT/mTOR signalling. Gain- and loss-of-function experiments supported a growth-promoting role for FABP6L in cultured ccRCC cells and xenografts, while genetic rescue experiments indicated a major contribution of PTEN to the signalling and growth phenotypes. In preclinical models with reduced everolimus sensitivity, FABP6L depletion increased PTEN abundance and enhanced the response to mTOR inhibition. The findings support an isoform-specific mechanism connecting FABP6L to PTEN turnover and ccRCC growth. They also provide a basis for investigating FABP6L-directed approaches to improve everolimus response, although their clinical relevance requires further validation.