Role of Ferroptosis in Alveolar Epithelial Cells in Acute Respiratory Distress Syndrome

Abstract

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by the rapid onset of respiratory failure resulting from extensive inflammation and damage to the alveolar‒capillary barrier. ARDS can be triggered by various factors, including pneumonia, sepsis, trauma, and aspiration, emphasizing its relevance in the field of critical care medicine. Ferroptosis is a novel form of regulated cell death that plays a crucial role in the pathophysiology of ARDS. Unlike apoptosis and necrosis, ferroptosis is characterized by the lethal accumulation of lipid peroxides (LPOs), which is driven primarily by dysregulated iron metabolism and oxidative stress. Alveolar epithelial cells (AECs), pivotal in maintaining pulmonary homeostasis and gas exchange, exhibit heightened vulnerability to ferroptosis in ARDS. The inflammatory microenvironment associated with this syndrome further highlights the potential impact of ferroptosis on lung injury and repair processes. This review elucidates the multifaceted relationships among ferroptosis, inflammation, and oxidative stress in AECs, providing insights into the pathological mechanisms through which ferroptosis contributes to lung injury and the disruption of the alveolar‒capillary barrier. Furthermore, the therapeutic implications of targeting ferroptosis in ARDS management, including the roles of antioxidants and intracellular nutrients in mitigating oxidative damage and preserving lung function, are discussed. These mechanistic insights underscore ferroptosis as a tractable therapeutic node in ARDS pathobiology.

Keywords: acute respiratory distress syndrome; alveolar epithelial cells; antioxidants; ferroptosis; immune cells; inflammation; oxidative stress.

Figure 1

Mechanisms of Ferroptosis.

Figure 2

Ferroptosis, inflammation and oxidative stress in AECs. In early ARDS, oxidative stress, driven by reactive oxygen species (ROS), disrupts alveolar epithelial cell (AEC) integrity. Excessive ROS oxidizes polyunsaturated fatty acids (PUFAs), triggering lipid peroxidation (LPO) via ACSL4/LOX pathways, while depleting glutathione (GSH)/GPX4 antioxidant defenses. This results in iron overload, Fenton reaction activation, and ferroptosis, characterized by membrane lipid remodeling (4-HNE/MDA accumulation) and DAMPs release, which amplifies inflammation. In late ARDS, persistent ferroptosis reduces functional cell populations (AECs, endothelial cells, fibroblasts), impairing tissue repair. Ferroptosis sustains oxidative stress through TGF-β/SMAD signaling, promoting collagen deposition and myofibroblast differentiation.

Figure 3

Ferroptosis and immune cells in AECs.

Figure 4

Pharmacological antioxidants.

Figure 5

Targeting ferroptosis as a treatment strategy for ARDS.