Residual bile flow shapes PPARγ-mediated antifibrotic responses in experimental segmental cholestasis

Segmental cholestasis represents a clinically relevant but underexplored cause of progressive liver fibrosis, particularly in pediatric conditions associated with intrahepatic biliary strictures, where segmental obstruction promotes progressive fibro-inflammatory injury that extends into adjacent non-cholestatic parenchyma. The mechanisms determining regional therapeutic responsiveness in segmental cholestasis remain poorly defined. . Here, we investigated the effects of PPARγ agonism in a selective bile duct ligation (sBDL) model that reproduces key features of segmental cholestasis and the propagation of fibro-inflammatory signaling beyond the primary site of injury. Newly weaned Wistar rats underwent sBDL and were treated with the PPARγ agonist pioglitazone or vehicle. Cholestatic (CL) and non-cholestatic (NCL) liver lobes were analyzed at 7, 30, and 60 days post-surgery using histological, immunohistochemical, biochemical, transcriptomic, and gene co-expression network analyses. Therapeutic responsiveness was strongly region dependent. In non-cholestatic lobe (NCL-T), PPARγ activation reduced macrophage recruitment, ductular reaction, and collagen deposition, accompanied by downregulated inflammatory and TGF-β–related signaling pathways. Gene co-expression network analysis revealed that PPARγ activation showed a hierarchical gene network topology and functional modularity in treated non-cholestatic lobes, preventing the network collapse observed in vehicle-treated animals. In contrast, the cholestatic lobe (CL-T) showed limited transcriptional responsiveness and remained largely refractory to therapeutic modulation, consistent with a stabilized fibro-inflammatory microenvironment. These findings demonstrate that injury heterogeneity and partial preservation of bile flow critically determine of therapeutic responsiveness, supporting PPARγ activation as a preventive antifibrotic strategy to limit fibro-inflammatory propagation in vulnerable hepatic regions during segmental cholestasis.