Lycii radicis cortex alleviates fibrosis in hiPSC-derived multilineage hepatic organoids via the cAMP-PKA pathway.

BACKGROUND

Liver fibrosis, driven by excessive extracellular matrix (ECM) deposition and activation of hepatic stellate cells (HSCs), still lacks effective therapies, partly due to the absence of human-relevant models. Lycii Radicis Cortex (LRC), a traditional Chinese medicine, exhibits reported anti-inflammatory and antioxidant activities, yet its anti-fibrotic potential has not been validated in human organoid-based systems.

METHODS

We established hiPSC-derived multilineage hepatobiliary organoids (mHBOs) containing mesoderm-derived HSCs and implemented a TGF-β-induced fibrosis model within this platform. Using mHBOs alongside a CCl4-injury mouse model, we assessed the anti-fibrotic activity of LRC, and investigated underlying mechanisms.

RESULTS

LRC significantly attenuated fibrosis in mHBOs and in CCl4-injured mice, reducing ECM accumulation and HSC activation. In mHBOs, LRC activated the cAMP-PKA-CREB pathway, thereby suppressing HSC activation and reducing parenchymal apoptosis; these effects were reversed by PKA inhibition.

CONCLUSION

LRC exhibits potent anti-fibrotic activity in a physiologically relevant human organoid model, providing mechanistic insight into HSC regulation and supporting its potential as a candidate therapy for chronic liver disease. Furthermore, this study introduces a translational platform integrating animal models and hiPSC-derived organoids to facilitate anti-fibrotic drug discovery and evaluation.