Paroxetine attenuated liver fibrosis in liver of bile duct ligated rats: role of P2X

Hepatic fibrosis, a precursor to cirrhosis, arises from complex mechanisms, including hepatic stellate cell (HSC) activation, inflammatory cytokine release, and excessive extracellular matrix (ECM) deposition. Despite the significant clinical burden, there are currently no FDA-approved treatments available. This study aimed to evaluate the potential anti-fibrotic effects of paroxetine-an FDA-approved selective serotonin reuptake inhibitor (SSRI) commonly prescribed for anxiety-related disorders-by examining its influence on profibrotic gene expression and inflammatory mediators, with particular focus on the P2X4 receptor. Paroxetine (5, 10 mg/kg) was administered in a rat model of BDL-induced hepatic fibrosis. Liver pathology was assessed through histological analysis and measurement of serum transaminase levels. Expression levels of profibrotic markers-transforming growth factor-beta 1 (TGF-β1), α-smooth muscle actin (α-SMA), and collagen type I alpha 1 (COL1A1)-and inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and the expression of P2X4, a key purinergic receptor implicated in fibrosis, were quantified using real-time PCR. Paroxetine treatment (10 mg/kg) significantly ameliorated liver pathology, reducing serum transaminase levels and hepatic expression of TGF-β1, α-SMA, and COL1A1. It markedly suppressed hepatic TNF-α and IL-6, indicating reduced inflammation. The most significant finding was that paroxetine significantly inhibited the upregulated levels of P2X4 in the BDL group, highlighting a critical pathway modulated by the drug. Paroxetine holds promise as a therapeutic candidate for hepatic fibrosis. Its ability to reduce profibrotic and inflammatory responses, alongside P2X4 inhibition, warrants further investigation into its clinical potential for managing liver fibrosis and cirrhosis.