Hepatic huntingtin loss drives an acute phase response and liver injury in multiple mouse models

Multiple therapeutic strategies are being developed to slow Huntingtons disease (HD) progression through targeted reduction of huntingtin (HTT) protein or mRNA. Despite HTTs discovery over 30 years ago, its cellular functions remain incompletely understood, and the long-term consequences of HTT-lowering therapies remain unclear. We previously demonstrated that hepatic HTT loss in mice disrupts hepatocyte zonation and metabolism. Here, we investigate the physiological consequences of hepatic Htt loss. Across multiple models of Htt loss--including ubiquitous and hepatocyte-specific genetic knockouts and a therapeutically relevant Htt-targeting siRNA--there was elevated expression of IL-6/STAT3-driven acute phase response genes. Single-nucleus RNA sequencing reveals a zonal pattern of hepatocyte stress, most highly upregulated in pericentral hepatocytes, and identifies a distinct pericentral cluster of stressed hepatocytes that was enriched [~]9.6-fold following Htt knockout. Histological examination reveals that Htt loss results in increased hepatic pathology, including hepatic intranuclear inclusions, apoptosis, and necrosis, as well as prevalence of granulomas. Transcriptomic analysis reveals significant upregulation of metallothionein genes following Htt loss, as confirmed by elevated plasma metallothionein-1 (MT1) levels in knockout mice. These findings underscore important safety considerations for HTT-lowering therapies and suggest candidate biomarkers for monitoring hepatic off-target effects in clinical trials.