Mechanistic ODE modelling of ovarian tumour microenvironment dynamics under hesperidin exposure

Abstract

Ovarian cancer progression is driven by complex interactions among tumour, immune, stromal, metabolic and angiogenic processes. Although hesperidin exhibits anti-cancer and immunomodulatory activities, its integrated effects on the tumour microenvironment (TME) remain insufficiently understood. This study presents a mechanistic ODE-based framework integrating tumour growth, immune regulation, macrophage polarization, cancer-associated fibroblast (CAF)-mediated extracellular matrix (ECM) remodelling, hypoxia-inducible factor (HIF)−1α/ vascular endothelial growth factor (VEGF)-dependent angiogenesis, glucose–lactate metabolism and redox signalling within a hypothetical ovarian TME centred on PA-1 cells. Simulations across multiple hesperidin concentrations predicted dose-dependent suppression of tumour growth, reduced HIF−1α accumulation, angiogenesis, ECM stiffening and lactate production, accompanied by enhanced anti-tumour immune activity. Local one-at-a-time (OAT) and global Sobol’ sensitivity analyses identified tumour growth kinetics, CAF–ECM interactions, metabolic regulation and selected hesperidin-response parameters as principal determinants of system behaviour. Although not calibrated for quantitative prediction, the proposed framework provides mechanistic insight into how hesperidin-mediated perturbations propagate through interconnected tumour–immune–stromal networks. The model should be regarded as an exploratory, hypothesis-generating platform supporting future experimental validation of hesperidin-mediated mechanisms in ovarian cancer.