Hijacking the Hydrogen Sulfide Axis: A Novel 4-Trifluoromethylquinoline Derivative Suppresses Glioblastoma via Cystathionine γ-Lyase Suppression.

Cystathionine γ-lyase (CTH) is markedly enriched in glioblastoma (GBM) and is associated with poor patient survival, enhanced temozolomide (TMZ) resistance, and aggressive phenotypes; however, effective CTH inhibitors for GBM therapy are currently lacking. Using click chemistry-based target identification, we identified cystathionine γ-lyase (CTH) as the direct molecular target of a novel 4-trifluoromethylquinoline derivative, TKL002. TKL002 exhibits strong antitumor activity both in vitro and in vivo, inducing late-stage apoptosis and G2/M cell cycle arrest. Mechanistically, TKL002 inhibits CTH activity, reduces hydrogen sulfide (H2S) production, suppresses NF-κB phosphorylation, and downregulates pro-inflammatory cytokine expression. In addition, TKL002 inhibits GBM cell migration and invasion by upregulating E-cadherin and downregulating N-cadherin and vimentin. Collectively, these findings demonstrate that TKL002 exerts potent antiglioblastoma activity via modulation of the CTH/H2S/NF-κB/EMT signaling axis, highlighting its potential as a quinoline-based therapeutic candidate to overcome intrinsic GBM resistance and invasiveness.