Glaucocalyxin A Induces Cytotoxicity in Renal Cancer Cells via ROS‐Mediated Autophagy by Direct Targeting of Antioxidant Enzymes PRDX1 and PRDX2

Abstract Glaucocalyxin A (GLA), a bioactive diterpenoid from the medicinal plant Rabdosia japonica , demonstrates potent antitumor activity, yet its molecular mechanisms in renal cell carcinoma (RCC) remain elusive. Here, GLA is reported to trigger cytotoxicity in RCC cells through reactive oxygen species (ROS) overaccumulation. Mechanistically, ROS surge activates autophagy, and pharmacological or genetic autophagy inhibition significantly rescues GLA‐induced cell death, indicating autophagy acts as a pro‐death effector in this context. Employing activity‐based protein profiling (ABPP) coupled with proteomic analysis, peroxiredoxins PRDX1/2 are identified as direct covalent targets of GLA. Functional validation reveals that PRDX1/2 overexpression mitigates GLA‐mediated apoptosis, establishing their role as critical redox sensors governing cell fate. The findings delineate a ROS‐autophagy‐apoptosis axis driven by PRDX1/2 targeting, positioning GLA as a novel therapeutic scaffold for RCC treatment.