Modification‐Selective Inhibition of Succinate Dehydrogenase a Enables Tumor‐Restricted Mitochondrial Modulation

ABSTRACT

Succinate dehydrogenase (SDH, complex II) connects the tricarboxylic acid (TCA) cycle to the electron transport chain (ETC), maintaining mitochondrial energy homeostasis. Selective SDH inhibition in diseased tissue has remained challenging due to the highly conserved catalytic architecture across normal tissues. Here, we reveal that SDH catalytic activity depends on the acetylation state of its catalytic subunit A (SDHA): the non‐acetylated form is catalytically active but exhibits fragile homeostasis in bladder cancer, contrasting with its robust maintenance in normal cells. Guided by this insight, we designed ZPI‐3, a conformationally optimized inhibitor that selectively engages the non‐acetylated SDHA, suppressing tumor SDH activity and growth while sparing normal cells. In orthotopic NMIBC models, ZPI‐3 outperforms mitomycin‐C. Differential SDH responses to ZPI‐3 in clinical specimens further suggest its potential for patient stratification and precision therapy. These findings establish modification‐selective inhibition as a paradigm for tumor‐selective mitochondrial modulation.