Thermal Proteome Profiling Strategy Identifies CNPY3 as a Cellular Target of Gambogic Acid for Inducing Prostate Cancer Pyroptosis

There
is an urgent requirement to acquire a comprehensive comprehension
of novel therapeutic targets for prostate cancer to facilitate the
development of medications with innovative mechanisms. In this study,
we identified gambogic acid (GBA) as a specific pyroptosis inducer
in prostatic cancer cells. By using a thermal proteome profiling (TPP)
strategy, we revealed that GBA induces pyroptosis by directly targeting
the canopy FGF signaling regulator (CNPY3), which was previously considered
“undruggable”. Moreover, through the utilization of
the APEX2-based proximity labeling method, we found that GBA recruited
delactatease SIRT1, resulting in the elimination of lysine lactylation
(Kla) on CNPY3. Of note, SIRT1-mediated delactylation influenced the
cellular localization of CNPY3 to promote lysosome rupture for triggering
pyroptosis. Taken together, our study identified CNPY3 as a distinctive
cellular target for pyroptosis induction and its potential application
in prostate cancer therapy.