Network pharmacology and molecular simulation study on the multi-target gene regulatory mechanism of Isatis indigotica against hepatic inflammation.

Osteoarthritis (OA) currently represents an escalating challenge for global healthcare systems, as one of the most prevalent musculoskeletal conditions and a primary cause of disability among adults [,]. The prevalence of OA continues to rise globally, driven primarily by an aging population and the growing obesity epidemic []. Consequently, the increasing incidence of OA translates into a substantial socioeconomic burden on healthcare systems worldwide, affecting millions of individuals and significantly reducing their functional independence [,]. Knee cartilage damage and the subsequent development of OA lead to a profound deterioration in patients' quality of life, particularly in the psychological and social domains, which is strongly correlated with pain intensity []. Furthermore, recent epidemiological data highlight that joint cartilage injuries are increasingly diagnosed in younger, physically active populations, challenging the traditional view of OA strictly as a disease of advanced age []. Within this context, running - as one of the most accessible and popular forms of physical activity, with over 30 million marathon participants annually - remains a subject of controversy among both the general public and clinicians [,]. A so-called "running paradox" emerges: despite the fact that this activity generates ground reaction forces exceeding eight times body weight and is associated with a high incidence of overuse injuries, numerous epidemiological studies indicate a neutral or even protective effect of running on articular cartilage [,]. While the traditional "wear and tear" model perceived cartilage as a passive structure undergoing simple mechanical wear, modern evidence indicates that OA is a multifaceted disease resulting from a complex interaction between biomechanical loading, inflammation, genetics, metabolic health, and previous injury []. Crucial to the understanding of this relationship is the introduction of a clear dichotomy regarding exercise intensity. Scientific literature distinguishes recreational running (leisure/amateur), typically defined as activity undertaken for health-related purposes at a moderate volume (e.g., below 40-50 km per week), from elite/competitive running, which encompasses professional athletes, international competitors, and individuals subjecting their joints to extreme loads (exceeding 92 km per week) []. The foundation of modern knowledge regarding joint health in runners is the concept of mechanotransduction. Living articular cartilage possesses the capacity for conditioning; molecular processes occurring within chondrocytes, modulated by mechanoreceptors (such as the α5β1 integrin), facilitate the adaptation of the extracellular matrix to cyclic loading, thereby enhancing its resistance to damage [,,].