Luteolin as a multi-targeted polyphenol in pulmonary fibrosis: network pharmacology, mechanistic insights, and formulation advances

Abstract Background Luteolin is a natural polyphenolic flavonoid (C 6 –C 3 –C 6 structure) found in various medicinal herbs. It exhibits significant antioxidant, anti-inflammatory, and anti-fibrotic properties, making it a promising therapeutic compound for fibrotic illnesses, including pulmonary fibrosis. The condition is distinguished by excessive extracellular matrix formation in lung tissue, resulting in stiffness and reduced respiratory performance. Current treatments, limited to nintedanib and pirfenidone, merely slow disease progression, highlighting the need for more effective therapeutic options. Main body Luteolin exerts its effects by modulating key signaling pathways, including transforming growth factor-beta/small mothers against decapentaplegic (TGF-β/SMAD), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), nuclear factor erythroid 2–related factor 2 (NRF2), signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase (MAPK), and NOD-like receptor family pyrin domain-containing 3 (NLRP3), thereby reducing oxidative stress, inflammation, and fibrosis. In vitro and pre-clinical studies also support its therapeutic potential. Furthermore, network pharmacology has identified multiple hub targets of luteolin and highlighted its synergistic interactions with other bioactive compounds. These interactions contribute to enhanced biological outcomes such as cell cycle deceleration, apoptosis induction, and angiogenesis inhibition in inflammatory conditions and cancers. However, poor bioavailability and targeted delivery challenges limit luteolin’s clinical utility. To overcome these issues, nanoparticle-based delivery systems, including nanosuspensions, solid lipid nanoparticles, and polymeric nanoparticles, have been developed to enhance their lung-targeted delivery and therapeutic efficacy. Conclusion This narrative review outlines luteolin’s multiple molecular targets, pathways, and mechanisms in modulating fibrotic diseases, especially lung fibrosis, and emphasizes the gap between current formulation strategies and clinical translation. Advanced delivery technologies hold promise for enhancing luteolin’s therapeutic value. Hence, additional investigation is needed to establish its effectiveness as well as its safety in clinical settings and develop luteolin as a viable treatment option for chronic respiratory diseases, particularly pulmonary fibrosis.