Lupeol induces apoptosis of glioma cells via governing ubiquitination-mediated SPARC turnover.

Glioblastoma multiforme (GBM) remains a lethal malignancy with limited therapeutic options due to its aggressive progression and resistance to apoptosis. SPARC (secreted protein acidic and rich in cysteine), a multifunctional glycoprotein implicated in glioma survival and chemoresistance, is stabilized by deubiquitinating enzymes (DUBs), yet the regulatory mechanisms driving its turnover are poorly defined. Lupeol, a natural triterpenoid, exhibits anticancer potential, but its effects on glioma and underlying molecular mechanisms remain elusive. Here, we demonstrate that lupeol induces apoptosis in glioma cells by targeting ubiquitination-mediated SPARC degradation. Mechanistically, lupeol enhanced SPARC polyubiquitination by disrupting its interaction with ubiquitin-specific protease 14 (USP14), a DUB that antagonizes proteasomal degradation of SPARC. These findings unveil a novel mechanism by which lupeol triggers apoptosis through USP14-dependent SPARC ubiquitination and degradation, highlighting the therapeutic potential of targeting the USP14-SPARC axis in glioma treatment. This study provides the first evidence linking lupeol's anticancer activity to ubiquitination-regulated protein turnover, offering insights for developing SPARC-directed therapies against gliomas.