Scoparone attenuates ethanol-induced hepatocellular injury through PI3K/Akt-mediated regulation of oxidative stress and apoptosis

AI Summary

Scoparone (SCO) protects ethanol-exposed HepG2 hepatocytes by activating the PI3K/Akt signalling pathway.
PI3K/Akt activation enhances Nrf2/HO-1 antioxidant defence and suppresses phosphorylated FoxO1-associated apoptotic signalling.
SCO restores mitochondrial membrane potential, attenuates oxidative stress, enhances alcohol metabolism; effects are reversed by PI3K inhibitor LY294002.

TL;DR (AI Generated)

KEY FINDINGS: Network pharmacology identified 109 overlapping targets between SCO and ALD, with the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway emerging as a key pathway.

Mechanistically, SCO activated PI3K/Akt signaling, thereby enhancing nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) antioxidant signaling and suppressing the phosphorylated forkhead box O1 (FoxO1)/FoxO1-associated apoptotic signaling.

Basic summary

J Pharm Pharmacol. 2026 Nov 4;78(11):rgag143. doi: 10.1093/jpp/rgag143.

ABSTRACT

OBJECTIVES: Scoparone (SCO) has demonstrated hepatoprotective potential in previous studies, whereas its molecular mechanisms against alcohol-associated liver disease (ALD) remain unclear. This study investigated the protective effects and underlying mechanisms of SCO in ethanol-induced HepG2 cells.

METHODS: Network pharmacology and molecular docking were employed to predict the potential targets and signaling pathways of SCO against ALD. Ethanol-induced HepG2 cells were used to validate the predicted mechanisms by biochemical assays, flow cytometry, immunofluorescence staining, quantitative real-time polymerase chain reaction and western blotting.

KEY FINDINGS: Network pharmacology identified 109 overlapping targets between SCO and ALD, with the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway emerging as a key pathway. SCO enhanced alcohol metabolism, attenuated oxidative stress, restored mitochondrial membrane potential, and suppressed ethanol-induced apoptosis. Mechanistically, SCO activated PI3K/Akt signaling, thereby enhancing nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) antioxidant signaling and suppressing the phosphorylated forkhead box O1 (FoxO1)/FoxO1-associated apoptotic signaling. These protective effects were markedly reversed by the PI3K inhibitor LY294002.

CONCLUSIONS: SCO protects against ethanol-induced hepatocyte injury by activating the PI3K/Akt signaling pathway, thereby enhancing Nrf2/HO-1-mediated antioxidant defense and suppressing FoxO1-associated apoptotic signaling. These findings provide preliminary mechanistic evidence supporting further preclinical investigation of SCO in alcohol-associated liver injury.

PMID:43031540 | DOI:10.1093/jpp/rgag143

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