RESUMEN
BACKGROUND & AIMS: Liver fibrosis is the major driver for hepatocellular carcinoma and liver disease related death. Approved anti-fibrotic therapies are absent and compounds in development have limited efficacy. Increased TGF-ß signaling drives collagen deposition by hepatic stellate cells (HSC)/myofibroblasts. Here, we aimed to dissect the role of the circadian clock (CC) in controlling TGF-ß signaling and liver fibrosis. METHODS: Using CC-mutant mice, enriched HSCs and myofibroblasts obtained from healthy and fibrotic mice in different CC-phases and loss-of-function studies in human hepatocytes and myofibroblasts, we investigated the relationship between CC and TGF-ß signaling. We explored hepatocyte-myofibroblast communication through bioinformatic analyses of single-nuclei transcriptomes and validation in cell-based models. Using mouse models for MASH fibrosis and spheroids from patients with liver disease, we performed proof-of-concept studies to validate pharmacological targetability and clinical translatability. RESULTS: We discovered that the CC-oscillator temporally gates TGF-ß signaling and this regulation is broken in fibrosis. We demonstrate that HSCs and myofibroblasts contain a functional CC with rhythmic expression of numerous genes, including fibrogenic genes. Perturbation studies in hepatocytes and myofibroblasts revealed a reciprocal relationship between TGF-ß-activation and CC perturbation, which was confirmed in patient-derived ex vivo and in vivo models. Pharmacological modulation of CC-TGF-ß signaling inhibited fibrosis in mouse models in vivo as well as patient-derived liver spheroids. CONCLUSION: The CC regulates TGF-ß signaling, and the breakdown of this control is associated with liver fibrosis in patients. Pharmacological proof-of-concept studies across different models uncover the CC as a therapeutic candidate target for liver fibrosis - a rising global unmet medical need. IMPACT AND IMPLICATIONS: Liver fibrosis due to metabolic diseases is a global health challenge. Many liver functions are rhythmic throughout the day being controlled by the circadian clock (CC). Here we demonstrate that the regulation of the CC is perturbed upon chronic liver injury and this perturbation contributes to fibrotic disease. By showing that a compound targeting the CC improves liver fibrosis in patient-derived models, this study provides a novel therapeutic candidate strategy to treat fibrosis in patients. Additional studies will be needed for clinical translation. Since the findings uncovers a previously undiscovered profibrotic mechanism and therapeutic target, the study is of interest for scientists investigating liver disease, clinical hepatologists and drug developers.
RESUMEN
Persistent liver injury triggers a fibrogenic program that causes pathologic remodeling of the hepatic microenvironment (i.e., liver fibrosis) and portal hypertension. The dynamics of gene regulation during liver disease progression and early regression remain understudied. Here, we generated hepatic transcriptome profiles in two well-established liver disease models at peak fibrosis and during spontaneous regression after the removal of the inducing agents. We linked the dynamics of key disease readouts, such as portal pressure, collagen area, and transaminase levels, to differentially expressed genes, enabling the identification of transcriptomic signatures of progressive vs. regressive liver fibrosis and portal hypertension. These candidate biomarkers (e.g., Tcf4, Mmp7, Trem2, Spp1, Scube1, Islr) were validated in RNA sequencing datasets of patients with cirrhosis and portal hypertension, and those cured from hepatitis C infection. Finally, deconvolution identified major cell types and suggested an association of macrophage and portal hepatocyte signatures with portal hypertension and fibrosis area.
RESUMEN
Hepatocellular carcinoma is usually detected late and therapeutic options are unsatisfactory. Despite marked progress in patient care, HCC remains among the deadliest cancers world-wide. While surgical resection remains a key option for early-stage HCC, the 5-year survival rates after surgical resection are limited. One reason for limited outcomes is the lack of reliable prognostic biomarkers to predict HCC recurrence. HCC prognosis has been shown to correlate with different systemic and pathological markers which are associated with patient survival and HCC recurrence. Liver inflammatory processes offer a large variety of systemic and pathological markers which may be exploited to improve the reliability of prognosis and decision making of liver surgeons and hepatologists. The following review aims to dissect the potential tools, targets and prognostic meaning of inflammatory markers in patients with resectable HCC. We analyze changes in circulant cellular populations and assess inflammatory biomarkers as a surrogate of impaired outcomes and provide an overview on predictive gene expression signatures including inflammatory transcriptional patterns, which are representative of poor survival in these patients.