Targeting TGF-β-driven fibrotic, epigenetic remodeling and Bax/Bcl-2 through polyphenol-exercise synergy: molecular implications for biomechanical impairment and rehabilitation in cancer.

Optimizing human activity through biomechanical efficiency is central not only to enhancing physical performance but also to restoring functional capacity in disease states. In cancer patients, tumor progression and treatment-related toxicities induce profound molecular and epigenetic alterations within the tumor-muscle-matrix axis, leading to fibrosis, muscle wasting, neuromuscular dysfunction, and impaired activity biomechanics. While exercise training remains a cornerstone intervention for improving activity quality and physical resilience, emerging evidence suggests that targeted nutritional strategies, particularly polyphenol supplementation, may modulate key oncogenic and fibrotic signaling pathways. Polyphenols, a diverse class of plant-derived bioactive compounds, exert potent antioxidant, anti-inflammatory, and epigenetic regulatory effects that influence TGF-β/SMAD signaling, microRNA expression, extracellular matrix remodeling, and mitochondrial function in cancer and skeletal muscle tissues. This review examines the molecular and epigenetic convergence of polyphenols and exercise in reprogramming tumor-muscle-matrix crosstalk, and discusses how these mechanisms translate into biomechanical dysfunction, injury susceptibility, and rehabilitation outcomes in cancer patients. By integrating data from preclinical oncology models, clinical studies in cancer populations, and mechanobiological research, we explore how combined nutritional-mechanical interventions may attenuate cancer-associated fibrosis, modulate inflammatory and epigenetic signatures, preserve muscle integrity, and improve functional activity capacity. We further propose that selective modulation of fibrotic and epigenetic pathways may reduce biomechanical impairment, enhance rehabilitation responsiveness, and mitigate injury risk during cancer survivorship. The concept of molecular-mechanobiological synergy provides a translational framework linking tumor biology to functional activity outcomes. Future interdisciplinary research should prioritize longitudinal, multimodal studies integrating epigenetic biomarkers, tumor-derived signaling mediators, and advanced biomechanical profiling in oncology settings to validate and personalize combined exercise-polyphenol strategies.