Regulatory Bottlenecks Linking HDL Dysfunction, Inflammation, and Oxidative Stress: A Petri Net-Based Systems...

High-density lipoprotein (HDL) is a multifunctional lipoprotein involved in lipid transport, immune regulation, and redox homeostasis. Chronic inflammation and oxidative stress alter HDL composition and function, promoting the formation of dysfunctional HDL particles, impairing cholesterol efflux, and contributing to cardiovascular disease progression. To investigate the regulatory mechanisms underlying these changes, we developed a Petri net-based model of HDL metabolism and extended it to represent inflammatory conditions and selected therapeutic interventions. As a literature-derived qualitative model, it provides a simplified systems-level representation of HDL metabolism and its interactions with inflammation and oxidative stress. Nevertheless, the model captures the essential processes governing these pathways. Using in silico knock-out analysis, we evaluated the impact of disabling individual processes on global network dynamics and identified key regulatory bottlenecks. Network control was highly uneven and concentrated within a limited set of transitions. Under inflammatory conditions, the dominant bottlenecks included reduced LCAT-mediated cholesterol esterification, adiponectin-dependent regulation, and oxidized HDL-associated activity, indicating that HDL dysfunction arises from a tightly interconnected immunometabolic network linking lipid metabolism, inflammation, and oxidative stress. Therapeutic interventions reorganized network control toward the inhibition of inflammation, the restoration of redox balance, and the reconstitution of HDL-mediated cholesterol export. Inhibition of inflammation and oxidation-reduction remained dominant regulatory nodes across pathological and therapeutic states, suggesting a core regulatory backbone of HDL metabolism. These findings demonstrate that inflammation and oxidative stress fundamentally reshape HDL network control and identify a limited set of regulatory bottlenecks that may represent promising targets for therapeutic intervention in cardiovascular and chronic inflammatory diseases. However, because the model represents a simplified qualitative abstraction of HDL biology, the identified bottlenecks should be interpreted as systems-level hypotheses requiring further experimental validation.