Atraric acid activates the FoxO3a/PINK1/Parkin signaling pathway to suppress chronic intermittent hypoxia-induced cardiac oxidative stress, inflammatory responses, and NLRP3 inflammasome activation

Oct 15, 2025Chemico-biological interactions

Atraric acid may reduce heart damage from repeated low oxygen by activating a protective cell cleanup pathway

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Abstract

Atraric acid (AA) treatment significantly alleviated CIH-induced cardiac damage in mouse models.

AA treatment reduced oxidative stress and mitochondrial dysfunction associated with chronic intermittent hypoxia (CIH).
The compound activated a specific cellular process that helps clear damaged mitochondria, known as mitophagy.
AA's cardioprotective effects were linked to the promotion of FoxO3a moving into the nucleus.
Inhibition of autophagy or enhancement of reactive oxygen species (ROS) reversed the protective effects of AA.
AA also inhibited the activation of an inflammatory pathway related to cell damage.

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Obstructive sleep apnea syndrome (OSAS)-induced cardiac injury is closely associated with chronic intermittent hypoxia (CIH), but its molecular mechanisms and potential intervention strategies require further exploration. Atraric acid (AA), a compound extracted from oakmoss, has garnered attention due to its anti-inflammatory and antioxidant properties. However, its protective effects on the cardioprotective effects in the context of CIH have not been systematically investigated. Through the establishment of CIH mouse models and H9C2 cell IH injury models, combined with histopathological analysis, mitochondrial function assessment, qPCR, immunofluorescence, and Western blot, the protective effects and molecular mechanisms of AA against CIH-induced myocardial injury were evaluated. Experimental groups included a control group, CIH group, and AA intervention groups with varying doses. AA treatment significantly alleviated CIH-induced cardiac damage, suppressed ROS accumulation, mitochondrial dysfunction, and oxidative stress, and activated Pink1/Parkin pathway-mediated mitophagy by promoting FoxO3a nuclear translocation. Meanwhile, AA inhibited NLRP3 inflammasome activation and inflammatory responses. The protective effects of AA were reversed by autophagy inhibition or ROS enhancement, suggesting an interaction mechanism between mitophagy and inflammation regulation. This study is the first to demonstrate that AA mitigates CIH-related myocardial injury by enhancing mitophagy via the FoxO3a-PINK1/Parkin pathway while synergistically suppressing oxidative stress and NLRP3 inflammasome activation. These findings provide novel therapeutic targets for OSAS-associated cardiac complications and establish a theoretical foundation for the clinical translation of AA, though further clinical validation is warranted.

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Atraric acid activates the FoxO3a/PINK1/Parkin signaling pathway to suppress chronic intermittent hypoxia-induced cardiac oxidative stress, inflammatory responses, and NLRP3 inflammasome activation

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