Molecular Mechanism of POSTN Mediating M2 Polarization of Kupffer Cells to Promote Hepatic Fibrosis

Background/Objectives: Liver diseases cause more than 2 million annual deaths globally, accounting for 4% of the total global mortality rate. Hepatic fibrosis (HF) acts as an indispensable pathological mediator in the progressive deterioration of chronic liver diseases. Thus, the identification of effective anti-fibrotic targets and rational development of corresponding therapeutic agents are expected to deliver profound clinical value for patients suffering from chronic liver disorders. Methods: An in vivo HF model was established to detect Kupffer cell (KC) polarization and periostin (POSTN) protein expression. In vitro, the CCK-8 (Cell Counting Kit-8) assay was applied to evaluate the regulatory effects of Postn-knockdown macrophages on LX-2 cell activity. Conditional knockout mice with Postn were constructed in vivo, and liver tissue samples were used for single-cell sequencing. Functional enrichment and cell differentiation prediction analyses were performed. CellChat was further utilized to characterize alterations in intercellular communication between Postn-deficient KCs and adjacent liver cells. Finally, POSTN-targeted inhibitors were screened and validated via virtual drug screening and experiments. Results: In the HF model, the M2 polarization of KCs was associated with the upregulated expression of POSTN. In contrast, in vitro Postn knockdown correlated with significantly suppressed LX-2 cell activation. Single-cell profiling suggests that Postn deficiency in Kupffer cells is linked to remodeling of the hepatic microenvironment. In drug repurposing, Rhodiosin exhibited binding affinity to POSTN and was observed to inhibit macrophage M2 polarization. Conclusions: POSTN may contribute to KC M2 polarization and be associated with remodeling of the intercellular interaction network among liver cells. Rhodiosin, as a POSTN-binding compound, shows potential for anti-hepatic fibrotic effects.