Targeting the liver clock improves fibrosis by restoring TGF-β signaling

Area of Science:

• Hepatology
• Molecular Biology
• Chronobiology

Background:

• Liver fibrosis, a precursor to liver cancer and death, lacks effective treatments.
• Transforming growth factor-beta (TGF-β) signaling drives fibrosis by promoting collagen deposition in hepatic stellate cells (HSCs).
• The circadian clock (CC) influences daily rhythms in liver function, but its role in fibrosis is unclear.

Purpose of the Study:

• To investigate the role of the CC in regulating TGF-β signaling and liver fibrosis.
• To explore the therapeutic potential of targeting the CC-TGF-β axis.

Main Methods:

• Utilized CC-mutant mice, isolated HSCs/myofibroblasts from healthy and fibrotic mice, and human cell models.
• Performed bioinformatic analysis of single-nuclei transcriptomes to study cell communication.
• Validated findings in mouse models of metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis and patient-derived liver spheroids.

Main Results:

• Identified that the CC temporally gates TGF-β signaling, a process disrupted in fibrosis.
• Demonstrated that HSCs and myofibroblasts possess a functional CC with rhythmic expression of fibrogenic genes.
• Showed a reciprocal relationship between TGF-β activation and CC perturbation, confirmed in patient models.
• Pharmacological CC modulation inhibited fibrosis in vivo and in patient-derived models.

Conclusions:

• The CC's regulation of TGF-β signaling is critical, and its disruption is linked to human liver fibrosis.
• The CC represents a novel therapeutic target for liver fibrosis, addressing a significant unmet medical need.
• Targeting the CC offers a promising strategy for treating liver fibrosis, with potential for clinical translation.