Ferroptosis at the Crossroads of Redox Biology: Mechanisms, Regulators, and Therapeutic Opportunities

Abstract

Cellular death is a multifaceted process involving regulated (RCD) and accidental (ACD) mechanisms. While apoptosis has been extensively studied as a form of regulated cellular death, recent attention has shifted towards exploring non-apoptotic cell death pathways, particularly in the context of cancer treatment where resistance to apoptosis is common. Ferroptosis, a form of cell death dependent on iron and regulated by lipid peroxidation, has emerged as a novel mechanism distinct from apoptosis and necrosis. This review delves into the current understanding of ferroptosis, its regulatory processes, and its implications in various disease pathologies.

Ferroptosis is characterized by the accumulation of lipid peroxides and the involvement of labile iron, setting it apart from other forms of cell death. Dysregulation of lipid membrane integrity and overoxidation of polyunsaturated fatty acids are key features that contribute to membrane rupture and cell demise. Central to the orchestration of ferroptosis are regulatory proteins such as glutathione peroxidase 4 and iron-associated signaling pathways.

A critical interplay between reactive oxygen species (ROS) and ferroptosis dictates the balance between cellular damage and protection. ROS function as double-edged swords, serving as essential signaling molecules for various physiological processes while also posing a threat through oxidative damage to biomolecules. The intricate relationship between ROS, lipid peroxidation, and ferroptotic cell death underscores the importance of maintaining redox homeostasis for cell survival.

Several molecular players have been implicated in the regulation of ferroptosis, including the amino acid antiporter SLC7A11, glutathione peroxidase 4, and ferroptosis suppressor protein 1 (FSP1). These proteins play crucial roles in modulating cellular redox balance, lipid peroxidation, and susceptibility to ferroptotic stimuli. Understanding the interplay between these regulators provides insights into potential therapeutic targets for modulating ferroptosis in disease settings.

Moreover, metabolic pathways such as the trans-sulfuration pathway, nicotinamide adenine dinucleotide phosphate (NADPH) metabolism, and aldose reductase enzymes have been identified as key regulators influencing cellular sensitivity to ferroptosis. Targeting these pathways offers promising avenues for modulating ferroptotic cell death and mitigating oxidative damage in various disease states.

In conclusion, unraveling the intricate mechanisms of ferroptosis sheds light on novel avenues for therapeutic interventions targeting oxidative stress-related pathologies. By elucidating the molecular players and regulatory pathways governing ferroptotic cell death, researchers pave the way for innovative strategies aimed at modulating cellular redox balance and improving outcomes in disease states characterized by dysregulated cell death processes.