Curcumin Targets Crispld2 to Suppress Hepatic Stellate Cell Activation via PI3K/AKT Pathway Inhibition in Hepatic Fibrosis
Background & Aims Hepatic fibrosis (HF) is a key pathological process in the development of chronic liver disease, and the activation of hepatic stellate cells (HSCs) is its core driving factor. Although curcumin, as a natural polyphenolic compound, has therapeutic potential, its specific mechanism in HF is still unclear. Methods This study used the CCl4-induced mouse HF model and explored its mechanism through single-cell RNA sequencing (scRNA-seq) combined with in vitro and in vivo experimental systems. Results The results showed that curcumin attenuated liver injury and fibrosis levels in mice with HF in a dose-dependent way, alleviated liver pathological damage, improved liver function indicators, and inhibited the release of inflammatory factors. ScRNA-seq analysis revealed a significant reduction in the number of activated HSCs after curcumin treatment, and the key gene Crispld2 was identified through perturbation model prediction and pseudo-temporal analysis. Curcumin significantly downregulated the expression of Crispld2 and inhibited the activation of the PI3K/AKT signalling pathway. In the TGF—β—induced LX-2 cell activation model, curcumin inhibited HSC proliferation, promoted apoptosis, reduced fibrosis-related protein expression, and decreased inflammatory cytokine secretion by regulating Crispld2. Overexpression of Crispld2 reversed the anti-fibrotic effect of curcumin, while the PI3K/AKT pathway inhibitor LY294002 restored its therapeutic effect. Animal experiments further confirmed that curcumin improved HF by regulating the Crispld2/PI3K/AKT axis. Conclusions This study elucidates the molecular mechanism by which curcumin exerts anti-HF effects by inhibiting the activation of the PI3K/AKT pathway mediated by Crispld2, providing a new strategy for targeted therapy of Crispld2. Lay Summary This study investigated the ameliorative effects of curcumin, a natural compound, on hepatic injury and fibrosis in mouse models of liver fibrosis. The underlying mechanism involves the suppression of the key gene Crispld2, which subsequently blocks the aberrant activation of the PI3K/AKT signalling pathway, thereby inhibiting the activation of hepatic stellate cells and exerting hepatoprotective functions. These findings furnish novel scientific evidence supporting the therapeutic application of curcumin in patients with liver fibrosis and shed new light on the development of Crispld2-targeted pharmaceutical agents. Curcumin can alleviate liver injury and fibrosis in mice with hepatic fibrosis. The underlying mechanism is that curcumin blocks the PI3K/AKT signalling pathway by targeting and inhibiting Crispld2, thereby suppressing the activation of HSCs and ameliorating hepatic fibrosis.
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