Protein-State Editing through Proximity-Induced Targeted Delactylation

Selective manipulation of protein post-translational modifications without eliminating the modified proteins represents an emerging strategy for controlling protein function. Here, we introduce Delactylation Targeting Chimeras (DeLacTACs), a class of heterobifunctional molecules designed to redirect endogenous histone deacetylases (HDACs) toward lactylated proteins through chemically induced proximity. As a proof of concept, we targeted the oncogenic transcriptional coactivator YAP, whose lactylation at Lys90 promotes YAP–TEAD signaling. Through modular synthesis and systematic linker optimization, we developed a series of DeLacTACs and identified Y3CH and Y1PH as active compounds in gastric and liver cancer cells. Immunoprecipitation and quantitative mass spectrometry demonstrated reduced YAP K90 lactylation, accompanied by decreased lactylation of its transcriptional partner TEAD1 at Lys108 and Lys57, without substantial changes in their total protein abundance. Co-immunoprecipitation experiments further supported enhanced association between YAP and endogenous HDAC machinery following DeLacTAC treatment. These molecular changes were accompanied by reduced YAP nuclear accumulation, attenuated YAP–TEAD1 colocalization, suppression of downstream genes including CTGF, CYR61, and AARS1, and pronounced inhibition of tumor-cell proliferation and colony formation. The substantially weaker effects of the individual recognition components highlighted the importance of the bifunctional molecular architecture. Together, these findings establish DeLacTACs as a proximity-based chemical strategy for targeted modulation of protein lactylation and provide a foundation for programmable protein-state editing without target degradation.