Chen et al. discovered a highly potent and selective MLKL-targeted PROTAC C116 that effectively induces MLKL degradation and promotes parthanatos in HCC cells. More significantly, C116 was able to induce in vivo MLKL degradation and exerts anti-tumor activities in an orthotopic HCC tumor model, positioning it as a promising starting point for the treatment of HCC and a promising chemical probe for investigating the non-necroptotic functions of MLKL.