Combined quercetin with phosphodiesterase inhibitors; sildenafil and pentoxifylline alleviated CCl4-induced chronic hepatic fibrosis: Role of redox-sensitive pathways

Liver fibrosis is a common pathological condition that is caused by complicated molecular and cellular processes. This study evaluated the therapeutic potential of combined quercetin (QU) with either sildenafil (Sild) or pentoxifylline (PTX) in chronic carbon tetrachloride (CCl4)-induced liver fibrosis in Wistar albino rats. Fibrosis was induced by CCl₄ injections (1.5 mg/kg, i.p.) three times weekly for 10 weeks. After six weeks, rats received oral QU (50 mg/kg/day), Sild (50 mg/kg/day), or PTX (10 mg/kg twice/day) individually or in combination for the remaining four weeks. Results showed significant alterations in liver biochemical markers, histopathology, oxidative stress, inflammation, apoptosis, and hypoxic responses due to CCl₄ exposure. These changes included reduced expression of Nrf-2, HO-1, and cytoglobin, alongside increased levels of NF-κB, cleaved caspase-3, TNF-α, IL-1β, and HIF-1. Notably, QU, Sild, and PTX, individually or in combination, improved these parameters. The combination of QU with Sild or PTX proved more effective than single treatments, modulating anti-oxidant (Nrf2/HO-1/cytoglobin), anti-inflammatory (NF-κB/TNF-α), and hypoxic signaling pathways (HIF-1α). In conclusion, QU combined with phosphodiesterase inhibitors shows promise as a therapy for liver fibrosis, offering enhanced protection through anti-oxidants and anti-inflammatory mechanisms.