Abstract

Prolyl hydroxylase domain enzyme 1 (PHD1) is a key regulator of hypoxic adaptation and metabolic homeostasis, playing an important role in tissue damage and repair. To enable precise pharmacological interrogation of PHD1 function, we developed the first PHD1 degrader using proteolysis-targeting chimera (PROTAC) technology. Our lead compound, SH-26, a cereblon (CRBN)-recruiting PROTAC, induced PHD1 degradation in a concentration-, time-, and ubiquitin-proteasome system (UPS)-dependent manner across multiple cell lines. In an acetaminophen (APAP)-induced acute liver injury (ALI) model, SH-26 demonstrated protective effects, attenuating hepatic inflammation and necrosis without detectable cytotoxicity. Mechanistically, SH-26-mediated PHD1 degradation attenuated APAP-triggered reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and NLRP3 inflammasome activation, leading to robust in vivo protection against ALI. Collectively, our work identifies SH-26 as the first effective PHD1 degrader and demonstrates its utility as a chemical tool to dissect the pathological role of PHD1 in ALI.