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P7C3 targets eIF4A1 to alleviate hepatic fibrosis by inhibiting protein translation and autophagy in hepatic stellate cells

ABSTRACT: P7C3, an aminopropyl carbazole compound with established neuroprotective properties and therapeutic potential in neurodegenerative disorders, has demonstrated broad pharmacological activity across multiple pathologies. However, the effect of P7C3 on hepatic fibrosis remains unexplored. This research applied in vitro and in vivo systems to evaluate P7C3's antifibrotic efficacy. The findings demonstrated that P7C3 notably inhibited the proliferation of LX-2 cells and decreased the levels of the fibrotic markers collagen type alpha 1 (COL1A1) and fibronectin (FN). Eukaryotic initiation factor 4A1 (eIF4A1) was identified as a direct target of P7C3 through the integration of cellular thermal shift assay (CETSA) coupled with mass spectrometry and human protein microarray data, and subsequently validated using CETSA, drug affinity responsive target stability, and molecular docking analysis. P7C3 treatment markedly inhibited eIF4A1 levels in LX-2 cells, while eIF4A1 knockdown attenuated this effect by suppressing COL1A1 and FN expression. Mechanistically, P7C3 impaired global protein synthesis in hepatic stellate cells, including c-Myc, consistent with the outcomes observed following eIF4A1 silencing. Both eIF4A1 knockdown and P7C3 treatment significantly downregulated ULK1, induced accumulation of autophagic substrate p62, and increased LC3B-II/LC3B-I ratio, indicating potent disruption of autophagic flux via eIF4A1 targeting. Histopathological assessment of the liver tissues revealed that P7C3 significantly attenuated collagen deposition and architectural distortion in fibrotic mice. Concomitant improvements were observed in the hepatic function biomarkers, including serum ALT and AST levels, as well as in fibrotic markers (hydroxyproline content). Collectively, these findings delineate eIF4A1 as the primary target through which P7C3 alleviates hepatic fibrosis by suppressing protein translation and autophagic flux, providing mechanistic validation for advancing P7C3 as a promising antifibrotic agent.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316758 | GEO | 2026/01/21

REPOSITORIES: GEO

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Project description:Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer’s disease (AD). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of animal model of AD. Whole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Aβ-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 (SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR). Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of LC3B gene and turns on a prolonged transcription of SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and hypertrophic reactive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Ab aggregates in the brain of APP/PS1 mice An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients. Taken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.

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P7C3 targets eIF4A1 to alleviate hepatic fibrosis by inhibiting protein translation and autophagy in hepatic stellate cells

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