Targeting PYK2 with heterobifunctional T6BP helps mitigate MASLD and MASH-HCC progression

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The mechanisms underlying the regulation of hepatocyte non-receptor tyrosine kinases in metabolic dysfunction-associated steatohepatitis (MASH) remain largely unclear. Hepatocyte-specific overexpression or deletion and anti-protein tyrosine kinase 2 beta (PYK2) or anti-TRAF6-binding protein (T6BP) crosslinking were utilized to study fatty liver protection by T6BP. A P-PTC (peptide-proteolysis targeting chimera) degrades PYK2 to block MASH progression. We found that T6BP is a novel and critical suppressor of PYK2 that reduces hepatic lipid accumulation, pro-inflammatory factor release, and pro-fibrosis production. Mechanistic evidence suggests that T6BP directly targets PYK2 and prevents 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 by T6BP-recruiting CBL-mediated PYK2 degradation in a typical T6BP-dependent manner when the tiny fragment is specifically expressed using thyroxine binding globulin (TBG) vectors. This inhibits the progression of MASH, metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC (MASH-HCC), and metabolic syndrome in dietary rodent models. First-ever P-PTC based on the core segment of T6BP as a ligand for targeted recruitment of CBL targeting metabolic disorders like MASH has been devised and validated in animal models. Our study revealed a previously unknown mechanism: identification of T6BP as a key eliminator of fatty liver strongly contributes to the development of promising therapeutic targets, and the discovery of crucial fragments of T6BP-based pharmacon that interrupt PYK2 dimerization are novel and viable treatments for fatty liver and its advanced symptoms and complications. Excessive high-energy diet ingestion is critical in driving steatohepatitis via regulation of hepatocyte non-receptor tyrosine kinases. The mechanisms underlying the regulation of hepatocyte PYK2 in metabolic dysfunction-associated steatohepatitis remain largely unclear. Here, we found that T6BP as a critical fatty liver eliminator could be used for the development of promising therapeutic options. Additionally, vital T6BP-based pharmacon fragments that impede PYK2 dimerization have been found, offering new and effective treatments for advanced fatty liver symptoms and complications.