Natural therapeutics and traditional formulas targeting macrophage polarization in the fibrotic niche of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease driven by a self-perpetuating "fibrotic niche," where monocyte-derived alveolar macrophages (Mo-AMs) regulate disease progression. Conventional single-target antifibrotics show limited efficacy in reversing established fibrosis and frequently cause dose-limiting toxicities, prompting the investigation of natural product-based therapeutics as multi-targeted investigational alternatives. This narrative review examines the mechanisms through which purified phytochemicals and multicomponent botanical formulas modulate the pulmonary fibrosis (PF) immune microenvironment. Moving beyond the classical M1/M2 dichotomy, we outline the spatiotemporal heterogeneity of macrophages and their bidirectional crosstalk with myofibroblasts. We summarize preclinical and experimental pharmacological interventions targeting macrophage reprogramming networks, detailing how natural monomers exhibit targeted immunomodulation, including immunometabolic shifts (e.g., covalent GAPDH inhibition to suppress glycolysis) and mechanotransduction blockade (e.g., Piezo1 inhibition by specific terpenoids). Concurrently, quality-controlled botanical formulas demonstrate potential synergistic effects in modulating microenvironmental homeostasis. Natural product-based therapeutics provide a promising investigational approach for modulating the fibrotic niche. To address the translational gap in this field, future research requires a methodological shift from theoretical network pharmacology to empirical validation using raw metabolomics and spatial transcriptomics, integrated with macrophage-targeted nano-delivery systems and rigorous chemical fingerprinting.