Jianpi Huayu decoction alleviates hepatic fibrosis involving coordinated modulation of PPARα-mediated lipid metabolic reprogramming and the ROCK pathway

Background: Hepatic fibrosis is a critical stage in the progression from chronic liver injury to hepatocellular carcinoma (HCC), yet effective therapeutic options remain limited. Jianpi Huayu Decoction (JPHY) has been used clinically in patients with HCC accompanied by hepatic fibrosis, but its anti-fibrotic mechanisms remain unclear. This study evaluated the anti-fibrotic effects of JPHY and explored potential links between metabolic regulation and tissue mechanics.

Methods: A carbon tetrachloride (CCl₄)-induced mouse model of hepatic fibrosis and TGF-β-activated hepatic stellate cells were used to assess the anti-fibrotic effects of JPHY. Interventions included JPHY, the PPARα Agonist fenofibrate, and their combination. Multi-scale analyses were performed, including transcriptomic profiling, atomic force microscopy for local tissue stiffness measurement, molecular and cellular assays, and molecular docking and dynamics simulations. Clinical relevance was evaluated using human liver tissues. An orthotopic HCC model established in a fibrotic background was used to evaluate the association between JPHY treatment and tumor progression.

Results: JPHY attenuated CCl₄-induced hepatic fibrosis in mice, as evidenced by reduced Collagen deposition, decreased liver stiffness, and improved liver function parameters. Mechanistic analyses revealed that these effects were associated with activation of the PPARα-mediated lipid metabolic pathway and suppression of ROCK-dependent mechanical signaling. Combined treatment with JPHY and a PPARα Agonist resulted in greater improvements in anti-fibrotic markers than either treatment alone. Exploratory clinical validation suggested an inverse association between hepatic PPARα expression and fibrosis severity. In a fibrosis-associated HCC model, JPHY also suppressed tumor progression, accompanied by alterations in arachidonic acid metabolism.

Conclusion: JPHY alleviates hepatic fibrosis through coordinated modulation of PPARα-mediated metabolic remodeling and ROCK-dependent mechanical signaling, thereby reducing liver stiffness and extracellular matrix accumulation, with potential implications for mitigating fibrosis-associated HCC progression.