Reconfiguring the macrophage-centric intercellular network in pulmonary fibrosis: Emerging perspectives and therapeutic opportunities

pro-fibrotic macrophages, which significantly contribute to the remodeling of the pro-fibrotic pathological microenvironment within the lungs. At the same time, as a critical node in intercellular communication, establishing a bidirectional regulatory network with alveolar epithelial cells, fibroblasts, endothelial cells, and various immune cells. Through signaling mediators such as cytokines, exosomes, and apoptotic bodies, macrophages contribute to the regulation of epithelial-mesenchymal transition (EMT), fibroblast activation, endothelial-to-mesenchymal transition (EndMT), and the disruption of immune homeostasis. Collectively, these interactions play a pivotal role in the initiation and progression of diseases. Currently, only nintedanib, pirfenidone, and the novel phosphodiesterase 4B (PDE4B) inhibitor nerandomilast have received regulatory approval for clinical use. While these agents can slow the progression of lung function decline, they are unable to reverse established fibrotic lesions. Furthermore, numerous candidate drugs targeting single molecular pathways have failed to advance beyond phase II/III clinical trials due to inadequate efficacy or safety concerns. The emerging generation of investigational therapies primarily targets macrophage function remodeling, epithelial repair, and fibroblast inhibition; however, most remain in early clinical trial phases without significant breakthroughs to date. Consequently, there is an urgent clinical demand for more effective and safer therapeutic alternatives. In this context, natural plant-derived active ingredients, due to their ability to target multiple molecular pathways, offer a promising strategy for intervening in this complex network. Existing preclinical studies suggest that certain active compounds (such as quercetin, brusatol, licochalcone B, and salvianolic acid B) can regulate macrophage-associated processes, such as polarization, autophagy, or inflammatory responses, depending on the specific compound and experimental context. These compounds also improve the microenvironment of experimental fibrosis by attenuating pro-fibrotic signaling between macrophages and epithelial cells, fibroblasts, endothelial cells, and immune cells. However, it is important to note that most of this evidence is derived from in vitro and animal studies, and the precise molecular targets, multi-component synergistic mechanisms, and clinical translational potential of these compounds still require systematic validation. Therefore, this article provides a systematic review of the biological characteristics and subgroup heterogeneity of lung macrophages. It elucidates the underlying mechanisms by which the macrophage-centered multicellular interaction network contributes to the progression of PF. Additionally, the article summarizes currently approved Western medications, clinical failures, and the challenges associated with the development of novel targeted agents. Emphasis is placed on reviewing the pharmacological mechanisms and recent advances in natural active compounds targeting this core cellular network to intervene in PF. The objective is to offer a theoretical foundation for a more comprehensive understanding of PF pathogenesis and to facilitate the optimization and innovation of anti-fibrotic therapeutic strategies.