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

Abstract

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, <b>TKL002</b>. <b>TKL002</b> exhibits strong antitumor activity both in vitro and in vivo, inducing late-stage apoptosis and G₂/M cell cycle arrest. Mechanistically, <b>TKL002</b> inhibits CTH activity, reduces hydrogen sulfide (H₂S) production, suppresses NF-κB phosphorylation, and downregulates pro-inflammatory cytokine expression. In addition, <b>TKL002</b> inhibits GBM cell migration and invasion by upregulating E-cadherin and downregulating N-cadherin and vimentin. Collectively, these findings demonstrate that <b>TKL002</b> 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.