Cell death-induced chronic inflammation as a therapeutic target for metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by hepatic steatosis, inflammation, and fibrosis, which can ultimately lead to cirrhosis and hepatocellular carcinoma. Although recent Food and Drug Administration approvals of resmetirom and semaglutide mark a milestone in MASH therapy, no approved agents directly target hepatic inflammation or fibrosis, underscoring the urgent need for novel therapeutic strategies. Hepatocyte death is a histological hallmark that distinguishes MASH from simple steatosis, yet the mechanisms by which it drives chronic inflammation and fibrosis remain incompletely understood. We identified hepatic crown-like structures (CLSs), aggregates of macrophages surrounding dead hepatocytes, as the histological hub of this process. In steatotic livers, impaired dead cell clearance allows sustained macrophage-dead cell interactions within CLSs, where tissue-resident macrophages acquire profibrotic properties. Cholesterol accumulation in hepatocytes promotes cholesterol crystallization, triggering hepatocyte death and subsequent lysosomal cholesterol overload in CLS-constituting macrophages, thereby accelerating inflammation and fibrosis. Targeting this pathway using a liver-tropic supramolecular β-cyclodextrin polyrotaxane (βCD-PRX), which selectively delivers βCD to lysosomes via endocytosis, ameliorated macrophage lysosomal stress and hepatic fibrosis in murine MASH models without affecting body weight or steatosis. Beyond the liver, CLS-driven chronic inflammation contributes to adipose tissue dysfunction in obesity and the transition from acute kidney injury to chronic kidney disease, suggesting broad therapeutic relevance. Continued investigation of CLSs as a shared pathological microenvironment across metabolic diseases may pave the way for novel diagnostic and therapeutic modalities for MASH and related conditions.