Coelenterazine alleviates sepsis-associated acute kidney injury by inhibiting ferroptosis via the USP14-NCOA4 pathway.

Background: Sepsis-associated acute kidney injury (S-AKI) is a frequent and severe complication of sepsis driven by systemic inflammation, oxidative stress, and vascular dysfunction, culminating in renal tubular injury and impaired excretory function. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation and reactive oxygen species (ROS) accumulation, is increasingly recognized as a key mechanism in S-AKI. Protective factors such as glutathione peroxidase 4 (GPX4) and the cystine/glutamate antiporter (SLC7A11) suppress ferroptosis-mediated renal damage. This study aimed to evaluate whether coelenterazine (CTZ), a marine-derived antioxidant, inhibits ferroptosis to mitigate S-AKI and to elucidate its underlying molecular mechanism. Methods: We investigated the effects of CTZ on oxidative stress and ferroptosis in renal tubular epithelial cells and in the context of S-AKI by examining lipid peroxidation, intracellular glutathione (GSH) levels, and ROS accumulation. Mechanistic studies focused on the role of ubiquitin-specific protease 14 (USP14) and modulation of the nuclear receptor coactivator 4 (NCOA4) pathway, with attention to ferroptosis-related regulators including GPX4 and SLC7A11. Results: CTZ attenuated oxidative stress and inhibited ferroptosis in renal tubular epithelial cells by targeting USP14 and modulating the NCOA4 pathway. This intervention reduced lipid peroxidation, restored intracellular GSH levels, and decreased ROS accumulation. CTZ's ferroptosis-suppressive effects were associated with preservation of GPX4/SLC7A11-mediated antioxidant defenses, leading to amelioration of S-AKI progression. Conclusions: CTZ functions as a novel inhibitor of ferroptosis in S-AKI by targeting USP14 and regulating the NCOA4 pathway, thereby reducing lipid peroxidation, restoring GSH, and limiting ROS accumulation. These findings identify CTZ as a promising therapeutic candidate for S-AKI and underscore the broader potential of ferroptosis inhibition in sepsis-induced organ dysfunction.