Phytochemicals modulating TGF-β signaling in radiation-induced fibrosis

Transforming growth factor-beta (TGF-β) is a central mediator of the pathogenesis of radiation-induced tissue injury, contributing to processes such as chronic inflammation, fibrosis, and immunosuppression. This review addresses the therapeutic potential of phytochemicals (bioactive plant-derived compounds) as potential agents to target and modulate TGF-β-mediated radiation-induced damage. A diverse group of phytochemicals, including curcumin, resveratrol, epigallocatechin gallate, quercetin, berberine, honokiol, and silibinin, exhibit potential multi-target effects on this pathway. Their reported effects are associated with modulation of Smad2/3 phosphorylation and nuclear translocation, and may involve regulation of TGF-β receptor expression and modulation of downstream non-canonical pathways such as MAPK and PI3K/Akt. Collectively, these actions may attenuate key pathological processes, including fibroblast-to-myofibroblast transition, epithelial-mesenchymal transition, excessive extracellular matrix deposition, and oxidative stress. Preclinical evidence from in vitro and in vivo models suggests that these compounds may reduce fibrosis and inflammation markers, such as collagen, α-SMA, and TGF-β1 itself; however, the majority of mechanistic evidence derives from non‑radiation fibrosis models (e.g., bleomycin, CCl₄, silica) and requires direct validation in radiation‑specific settings. Early-stage clinical trials, mostly small-scale and uncontrolled, have reported preliminary signals of reduced severity of radiation dermatitis and mucositis; however, these findings require confirmation in larger, well-designed trials. By modulating the profibrotic TGF-β axis, these compounds may represent potential supportive strategies for limiting radiation-induced normal-tissue injury; however, their clinical benefit, safety, and effects on tumor control remain to be established in adequately powered clinical studies.