Targeting PYK2 with heterobifunctional T6BP helps mitigate MASLD and MASH-HCC progression by Minxuan Xu & Junjie Zhao & Liancai Zhu & Chenxu Ge & Yan Sun & Ranran Wang & Yuanyuan Li & Xianling Dai & Qin Kuang & Linfeng Hu & Jing Luo & Gang Kuang & Yanrong Ren & Bochu Wang & Jun Tan & Shengbin Shi instant download

Targeting PYK2 with heterobifunctional T6BP helps mitigate MASLD and MASH-HCC progression by Minxuan Xu & Junjie Zhao & Liancai Zhu & Chenxu Ge & Yan Sun & Ranran Wang & Yuanyuan Li & Xianling Dai & Qin Kuang & Linfeng Hu & Jing Luo & Gang Kuang & Yanrong Ren & Bochu Wang & Jun Tan & Shengbin Shi instant download

Background & Aims: The mechanisms underlying the regulation of hepatocyte non-receptor tyrosine kinases in metabolicdysfunction-associated steatohepatitis (MASH) remain largely unclear.Methods: Hepatocyte-specific overexpression or deletion and anti-protein tyrosine kinase 2 beta (PYK2) or anti-TRAF6-bindingprotein (T6BP) crosslinking were utilized to study fatty liver protection by T6BP. A P-PTC (peptide-proteolysis targeting chimera)degrades PYK2 to block MASH progression.Results: We found that T6BP is a novel and critical suppressor of PYK2 that reduces hepatic lipid accumulation, proinflammatory factor release, and pro-fibrosis production. Mechanistic evidence suggests that T6BP directly targets PYK2 andprevents its N-terminal FERM domain-triggered dimerization, disrupting downstream PYK2-JNK signaling hyperactivation.Additionally, T6BP favorably recruits CBL, a particular E3 ubiquitin ligase targeting PYK2, to form a complex and degrade PYK2.T6BP (F1), a core fragment of T6BP, directly blocks N-terminal FERM domain-associated dimerization of PYK2, followed byT6BP-recruiting CBL-mediated PYK2 degradation in a typical T6BP-dependent manner when the tiny fragment is specificallyexpressed using thyroxine binding globulin (TBG) vectors. This inhibits the progression of MASH, MASH-related hepatocellularcarcinoma, and metabolic syndrome in dietary rodent models. We devised, and validated in animal models, the first-ever P-PTCbased on the core segment of T6BP, as a ligand for the targeted recruitment of CBL, that could be used to target metabolicdisorders like MASH.Conclusions: Our study uncovered a previously unknown mechanism, with T6BP identified as a key suppressor of steatosis. This,alongside the discovery of crucial T6BP-based fragments that interrupt PYK2 dimerization hold much promise for the treatmentof MASH.© 2024 European Association for the Study of the Liver. Published by Elsevier