Ferroptosis and pyroptosis: Mediating mechanisms of the cGAS/STING pathway and therapeutic strategies in heart failure
Zeyu Zhang, Zhihua Yang, Shuai Wang, Xianliang Wang, Jingyuan Mao
Abstract
Focusing on cardiomyocyte survival in the prevention and treatment of heart failure, ferroptosis and pyroptosis—two vital modes of cell death—have attracted intense interest. The immunomodulatory cGAS/STING axis, a currently prominent pathway, has also been found to mediate both ferroptosis and pyroptosis; however, the underlying mechanisms remain unclear. This review first traces the historical development of ferroptosis and pyroptosis, dissecting their distinctions, interconnections, and molecular biology. It then spotlights the cGAS/STING axis, elucidating the structural hallmarks of its core proteins, the cascade of signal activation and propagation, its self-amplifying feedback loop, and the precise routes through which it orchestrates ferroptosis and pyroptosis, while also revealing how these two death modalities in turn reinforce the pathway. Furthermore, we investigate the combined effects of ferroptosis and pyroptosis on cardiac structure and function, and rigorously evaluate emerging therapeutic strategies targeting the cGAS/STING axis, encompassing chemical drugs, bioactive natural compounds, small-molecule antagonists, genetic interventions, and exercise training. By integrating the axis’s dual role in counteracting pyroptosis and ferroptosis, the review highlights the cGAS/STING pathway as a central target in heart failure management, offering insights to advance both theoretical frameworks and practical therapeutic avenues. Significant breakthroughs have been achieved in the foundational experimental research on the cGAS/STING pathway. A series of pioneering findings has deeply elucidated the core mechanisms by which this pathway regulates ferroptosis and pyroptosis. Moreover, they have innovatively revealed the disruptive potential of various intervention strategies, including western medicines, inhibitors, and natural compounds, in treating heart failure by inhibiting this pathway to block ferroptosis and pyroptosis. These findings have substantial scientific value and broad translational potential. • Explains the mechanisms, differences, and connections between ferroptosis and pyroptosis. • Elucidate cGAS/STING biology and summarize its ferroptosis/pyroptosis-triggering mechanisms. • Strategies for regulating the cGAS/STING pathway to counter myocardial ferroptosis/pyroptosis have been integrated.