Abstract

Ethnopharmacological Relevance Shengxian Decoction (SXD) is a classical multi-herb prescription widely used in traditional Chinese medicine for chronic respiratory ailments. However, its pharmacological rationale and pro-resolving actions in idiopathic pulmonary fibrosis (IPF) have not been fully clarified. Aim of the Study : This study investigated the anti-fibrotic efficacy of SXD in a bleomycin (BLM)-induced mouse model and explored whether MerTK-dependent macrophage efferocytosis contributes to SXD-driven resolution. Materials and Methods Pulmonary fibrosis was induced by BLM in male C57BL/6 mice. Animals received SXD at two doses, with nintedanib (Nin) as a comparator; MerTK signaling was pharmacologically inhibited with UNC2025. Disease severity was evaluated by survival and body-weight changes, histology (H&E, Masson’s trichrome, Sirius Red), immunostaining (α-SMA, Ly6G, F4/80, CD68, MerTK), and molecular assays (RT-qPCR, ELISA, western blot). SXD constituents were profiled by LC-MS. Candidate targets/pathways were explored via network pharmacology and lung transcriptomics (RNA-seq). Macrophage efferocytosis was quantified in lung sections (TUNEL/CD68) and in vitro using BALF-derived macrophages co-cultured with fluorescently labeled apoptotic neutrophils. Results SXD mitigated BLM-induced fibrosis, improving survival and limiting weight loss, while reducing Ashcroft scores, collagen accumulation, α-SMA production, and profibrotic factors (including Tgf-β , Pdgf-α , and Mmp12 ); the high-dose regimen produced the most pronounced benefit. SXD also blunted early inflammation by decreasing Ly6G + neutrophil and F4/80 + macrophage recruitment and lowering TNF-α, IL-6, and IL-1β. LC-MS revealed a chemically complex formulation enriched in terpenoid components, and integrative network/RNA-seq analyses implicated multiple inflammation-fibrosis signaling programs. Mechanistically, SXD enhanced macrophage efferocytosis and increased MerTK and IL-10 expression; t