HMGB1 Mediates Hepatic Ferroptosis and Fibrosis Triggered by Echinococcus granulosus Infection

Abstract (1) Background: Cystic echinococcosis (CE), caused by Echinococcus granulosus ( E. granulosus ), is a globally distributed zoonosis predominantly affecting the liver. Persistent infection provokes chronic inflammation, hepatocellular injury, and fibrotic cyst formation, yet the molecular mechanisms remain incompletely defined. High-mobility group box 1 (HMGB1), a damage‑associated molecular pattern, regulates inflammation, oxidative stress, and ferroptosis. This study investigated whether HMGB1 coordinates an inflammation-ferroptosis-fibrosis axis during E. granulosus -induced liver injury. (2) Methods: We examined HMGB1 using liver tissues from naturally infected sheep, an infected rat model, and in vitro BRL hepatocytes and HSC‑T6 stellate cells. Histopathological injury, collagen deposition, and iron accumulation were assessed by staining. HMGB1, Fe²⁺, lipid peroxides, glutathione, superoxide dismutase, and malondialdehyde were quantified, and ferroptosis‑, inflammation‑, and fibrosis‑related proteins were analyzed. Glycyrrhizic acid (GA) and ferrostatin‑1 (Fer‑1) were used for intervention. (3) Results: Infection increased HMGB1 expression and release, promoted hepatic iron accumulation and lipid peroxidation, impaired antioxidant defenses, downregulated GPX4 and SLC7A11, and upregulated TFRC. It also activated TLR4/MYD88 and TGF‑β/Smad signaling, induced hepatic stellate cell activation, and enhanced collagen deposition. Iron‑positive regions overlapped with fibrotic areas. Inhibition of HMGB1 or ferroptosis corrected iron‑metabolism abnormalities, attenuated oxidative stress, and suppressed inflammatory and fibrotic responses; GA exerted broader protection. Exogenous HMGB1 further aggravated hepatocyte ferroptosis and promoted stellate activation. (4) Conclusions: HMGB1 functions as an upstream regulator linking E. granulosus ‑induced injury to ferroptosis, inflammation, and fibrosis. Targeting HMGB1 or ferroptosis may represent a promising therapeutic strategy for hepatic CE.