Caesalpinia Sappan Wood Extract Alleviates Ferroptosis-Like Oxidative Injury and Restores Macrophage Polarization Balance in Iron Overload-Induced Liver Fibrosis in Rats.

Iron overload-induced liver fibrosis involves interconnected pathological drivers: ferroptosis-like oxidative injury and dysregulated macrophage polarization. Although Caesalpinia sappan L. possesses well-characterized antioxidant and anti-inflammatory properties, its efficacy against this dual pathological axis has not been experimentally established. This study investigated the hepatoprotective effects of C. sappan wood extract (SWE) in an iron dextran-induced rat model of liver fibrosis. Male Wistar rats received intraperitoneal iron dextran (cumulative dose of 180 mg/kg BW over 39 days) to induce hepatic iron overload, followed by 28-day oral administration of SWE (25, 50, 75, or 100 mg/kg BW/day) or deferasirox (20 mg/kg BW/day). Hepatic iron concentration, liver function markers, oxidative stress parameters (MDA, SOD, and GPx4), macrophage polarization markers (CD86 and CD163), inflammatory and fibrogenic mediators (IL-6, IL-10, TGF-β1, and MMP-12), and fibrosis severity were assessed through biochemical, immunohistochemical, and histopathological analyses. SWE was standardized to 25.12% w/w brazilin by HPLC-PDA. SWE showed dose-related effects with optimal efficacy at intermediate doses, reducing hepatic iron burden, restoring GPx4 activity, suppressing lipid peroxidation, and enhancing antioxidant defense, collectively attenuating ferroptosis-like oxidative injury. Concurrently, SWE reduced M1 macrophage activation (decreased CD86 and IL-6) while promoting M2 polarization (increased CD163 and IL-10), suppressed TGF-β1-driven fibrogenesis, and restored MMP-12-mediated matrix remodeling, resulting in significant reductions in collagen deposition and fibrotic area. SWE performed comparably to deferasirox across most endpoints, with superior MMP-12 recovery. SWE simultaneously attenuates ferroptosis-like oxidative injury and restores macrophage polarization balance, establishing it as a mechanistically coherent multitarget candidate for iron overload-induced liver fibrosis with translational potential beyond that of iron chelation alone.