Targeting DEP-1 to regulate ERK/PPARγ dephosphorylation: multi-omics unravels dehydrocavidine's mechanism for...

Hepatic fibrosis (HF) is a critical state in the pathological and physiological progression of chronic liver disease to cirrhosis. Dehydrocavidine (DC), a natural isoquinoline alkaloid from the folk hepatoprotective herb Corydalis tomentella Franch., was reported to possess an anti-acute liver injury and anti-HF activities with mechanisms remaining unclear.

This study aimed to systemically evaluate the therapeutic effect of DC on HF and to explore its target and regulatory mechanism.

The anti-HF effect of DC was studied in vitro and in vivo aproaches by the CCl₄-induced HF mouse model and TGF-β1-induced LX-2/HSC-T6 cells. Multi-omics including transcriptomics, metabolomics, and Lip-MS proteomics were employed to discover target and regulatory pathway of DC. Molecular docking, CETSA, DARTS, siRNA and chemical reagents were used to validate target and the pathway.

In vitro and in vivo, DC could significantly inhibit the activation of hepatic stellate cells (HSCs), reduce fibrous deposition, and demonstrate therapeutic effects on HF, including improving liver function and alleviating inflammation. Mechanistically, it was demonstrated that DC could target DEP-1 and dephosphorylate ERK1/2 and PPARγ to inhibite the activation of HSCs and alleviate HF.

Dehydrocavidine alleviates HF by targeting DEP-1, a previously unrecognized regulator in HF, and regulating ERK/PPARγ dephosphorylation, which not only elucidates the novel DEP-1/ERK-PPARγ axis as a distinct mechanistic pathway in HF, but also establish DEP-1 as a HF-specific molecular target for the first time, positioning DC as a promising candidate for HF treatment.