Targeting the fibrosis-inflammation-oxidative stress axis: multifaceted mechanisms of salidroside in chronic organ fibrosis

Abstract

Tissue fibrosis represents the common terminal pathological features of multiple chronic diseases, yet effective therapeutic agents capable of retarding fibrotic progression remain limited. This review systematically delineates the antifibrotic pharmacological profile of salidroside and elucidates its multi-target synergistic mechanisms across renal, hepatic, pulmonary, and cardiac fibrosis. Our comprehensive analysis reveals that salidroside exerts multifaceted antifibrotic effects through the integrated modulation of diverse signaling networks. Specifically, it concurrently suppresses pro-fibrotic pathways including TGF-β1/Smad, Wnt/β-catenin, and PI3K/Akt/mTOR to attenuate extracellular matrix deposition and myofibroblast activation; activates the Nrf2-Keap1 antioxidant axis and the AMPK/SIRT1/PGC-1α energy metabolism pathway to enhance mitochondrial biogenesis and scavenge reactive oxygen species; and blocks p38/JNK and NF-κB inflammatory cascades to reduce TNF-α, IL-6, and IL-1β secretion. Notably, SIRT1 serves as a central hub mediating the crosstalk between ferroptosis and autophagy via the SIRT1/PINK1 axis, while simultaneously coordinating antioxidant-anti-inflammatory amplification and bidirectional inhibition of fibrotic signaling, thereby forming positive-feedback loops that circumvent compensatory pathway activation inherent to single-target interventions. Furthermore, salidroside indirectly ameliorates fibrotic microenvironments through gut microbiota remodeling and modulation of gut-organ axis metabolites including LPS and TMAO. Despite these promising preclinical findings, the clinical translation of salidroside is constrained by poor oral bioavailability, limited organ-targeting specificity, and a paucity of large-scale clinical evidence. Collectively, these findings establish salidroside as a promising multi-target antifibrotic candidate and provide a comprehensive mechanistic framework for its development into a cross-organ precision therapeutic, while highlighting the urgent need for optimized delivery systems and rigorous clinical validation to bridge the gap between basic research and clinical application.